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Memórias do Instituto Oswaldo Cruz, Volume: 117, Published: 2022
  • Molecular mechanisms of action of trypanocidal and leishmanicidal drugs with focus on novel chemotherapeutic strategies: creation of a Brazilian multicentre working group Editorial

    Menna-Barreto, Rubem Figueiredo Sadok; dos Santos, André Luis Souza
  • Where the DNA hides... In praise of José Rodrigues Coura Editorial

    Brandão, Adeilton Alves
  • Significance of a neglected tropical disease: lessons from a paradigmatic case of ‘success in translation’ Review

    Morel, Carlos M

    Abstract in English:

    In a previous publication, I stressed the fundamental importance of research for improving health using as an example the control of Chagas disease in the Americas.(1) For that purpose, I analysed the major scientific breakthroughs and public health events from the 1909 discovery of Chagas disease and its causative pathogen, Trypanosoma cruzi, by Carlos Chagas,(2) through the successful control of its transmission by insect vectors in large regions of the Southern Cone countries in the 90s.(3) In the twenty years since that publication, Brazil and Latin American countries had to cope with a number of serious public health threats, old and new: (i) recrudescence of well-known diseases, such as dengue and yellow fever; (ii) emergence of viral diseases that had been restricted to other continents (Zika, Chikungunya); (iii) new epidemics (H1N1) or (iv) pandemics (COVID-19). Are there still some lessons from that success story against a neglected disease of the 90s that would be relevant today in the context of these recent challenges?
  • Trypanosoma cruzi genetic diversity: impact on transmission cycles and Chagas disease Review

    Zingales, Bianca; Bartholomeu, Daniella C

    Abstract in English:

    Trypanosoma cruzi, the agent of Chagas disease (ChD), exhibits remarkable biological and genetic diversity, along with eco-epidemiological complexity. In order to facilitate communication among researchers aiming at the characterisation of biological and epidemiological aspects of T. cruzi, parasite isolates and strains were partitioned into seven discrete typing units (DTUs), TcI-TcVI and TcBat, identifiable by reproducible genotyping protocols. Here we present the potential origin of the genetic diversity of T. cruzi and summarise knowledge about eco-epidemiological associations of DTUs with mammalian reservoirs and vectors. Circumstantial evidence of a connection between T. cruzi genotype and ChD manifestations is also discussed emphasising the role of the host’s immune response in clinical ChD progression. We describe genomic aspects of DTUs focusing on polymorphisms in multigene families encoding surface antigens that play essential functions for parasite survival both in the insect vector and the mammalian host. Such antigens most probably contributed to the parasite success in establishing infections in different hosts and exploring several niches. Gaps in the current knowledge and challenges for future research are pointed out.
  • Why do we still have not a vaccine against Chagas disease? Review

    Camargo, Erney Plessmann; Gazzinelli, Ricardo Tostes; Morel, Carlos Médicis; Precioso, Alexander Roberto

    Abstract in English:

    This review does not intend to convey detailed experimental or bibliographic data. Instead, it expresses the informal authors’ personal views on topics that range from basic research on antigens and experimental models for Trypanosoma cruzi infection to vaccine prospects and vaccine production. The review also includes general aspects of Chagas’ disease control and international and national policies on the subject. The authors contributed equally to the paper.
  • Emerging and reemerging forms of Trypanosoma cruzi transmission Review

    Shikanai Yasuda, Maria Aparecida

    Abstract in English:

    This review aims to update and discuss the main challenges in controlling emergent and reemergent forms of Trypanosoma cruzi transmission through organ transplantation, blood products and vertical transmission in endemic and non-endemic areas as well as emergent forms of transmission in endemic countries through contaminated food, currently representing the major cause of acute illness in several countries. As a neglected tropical disease potentially controllable with a major impact on morbimortality and socioeconomic aspects, Chagas disease (CD) was approved at the WHO global plan to interrupt four transmission routes by 2030 (vector/blood transfusion/organ transplant/congenital). Implementation of universal or target screening for CD are highly recommended in blood banks of non-endemic regions; in organ transplants donors in endemic/non-endemic areas as well as in women at risk from endemic areas (reproductive age women/pregnant women-respective babies). Moreover, main challenges for surveillance are the application of molecular methods for identification of infected babies, donor transmitted infection and of live parasites in the food. In addition, the systematic recording of acute/non-acute cases and transmission sources is crucial to establish databases for control and surveillance purposes. Remarkably, antiparasitic treatment of infected reproductive age women and infected babies is essential for the elimination of congenital CD by 2030.
  • The history of Chagas disease: reflections on science in action Review

    Kropf, Simone Petraglia; Lima, Nísia Trindade

    Abstract in English:

    Approaching from the perspective of the history and social studies of science, the article analyses some aspects of the early history of Chagas disease, from its discovery through initial research. It is our goal to show that historians of science can explore this topic as a way not only of remembering and narrating past events but also of examining the processes through which science is produced. To this end, we present five basic precepts that have guided historical and sociological studies of “science in action”: science as a collective endeavor, as a social activity, as a set of practices, as a process that involves controversies, and as a formative process. By examining the topic in the light of these five points, we demonstrate how the history of this successful research tradition can lead us to broader reflections about the complex dynamics interweaving science and society.
  • Different profiles and epidemiological scenarios: past, present and future Review

    Gorla, David E; Xiao-Nong, Zhou; Diotaiuti, Lileia; Khoa, Pham Thi; Waleckx, Etienne; Souza, Rita de Cássia Moreira de; Qin, Liu; Lam, Truong Xuan; Freilij, Hector

    Abstract in English:

    The multiplicity of epidemiological scenarios shown by Chagas Disease, derived from multiple transmission routes of the aetiological agent, occurring on multiple geo-ecobiosocial settings determines the complexity of the disease and reveal the difficulties for its control. From the first description of the link between the parasite, the vector and its domestic habitat and the disease that Carlos Chagas made in 1909, the epidemiological scenarios of the American Trypanosomiasis has shown a dynamic increasing complexity. These scenarios changed with time and geography because of new understandings of the disease from multiple studies, because of policies change at the national and international levels and because human movements brought the parasite and vectors to new geographies. Paradigms that seemed solid at a time were broken down, and we learnt about the global dispersion of Trypanosoma cruzi infection, the multiplicity of transmission routes, that the infection can be cured, and that triatomines are not only a health threat in Latin America. We consider the multiple epidemiological scenarios through the different T. cruzi transmission routes, with or without the participation of a Triatominae vector. We then consider the scenario of regions with vectors without the parasite, to finish with the consideration of future prospects.
  • The translational challenge in Chagas disease drug development Review

    Kratz, Jadel M; Gonçalves, Karolina R; Romera, Lavínia MD; Moraes, Carolina Borsoi; Bittencourt-Cunha, Paula; Schenkman, Sergio; Chatelain, Eric; Sosa-Estani, Sergio

    Abstract in English:

    Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.
  • Parasitological, serological and molecular diagnosis of acute and chronic Chagas disease: from field to laboratory Review

    Schijman, Alejandro Gabriel; Alonso-Padilla, Julio; Longhi, Silvia Andrea; Picado, Albert

    Abstract in English:

    There is no consensus on the diagnostic algorithms for many scenarios of Trypanosoma cruzi infection, which hinders the establishment of governmental guidelines in endemic and non-endemic countries. In the acute phase, parasitological methods are currently employed, and standardised surrogate molecular tests are being introduced to provide higher sensitivity and less operator-dependence. In the chronic phase, IgG-based serological assays are currently used, but if a single assay does not reach the required accuracy, PAHO/WHO recommends at least two immunological tests with different technical principles. Specific algorithms are applied to diagnose congenital infection, screen blood and organ donors or conduct epidemiological surveys. Detecting Chagas disease reactivation in immunosuppressed individuals is an area of increasing interest. Due to its neglect, enhancing access to diagnosis of patients at risk of suffering T. cruzi infection should be a priority at national and regional levels.
  • Chagas disease in the context of the 2030 agenda: global warming and vectors Review

    Souza, Rita de Cássia Moreira de; Gorla, David E; Chame, Marcia; Jaramillo, Nicolas; Monroy, Carlota; Diotaiuti, Lileia

    Abstract in English:

    The 2030 Agenda for Sustainable Development is a plan of action for people, planet and prosperity. Thousands of years and centuries of colonisation have passed the precarious housing conditions, food insecurity, lack of sanitation, the limitation of surveillance, health care programs and climate change. Chagas disease continues to be a public health problem. The control programs have been successful in many countries in reducing transmission by T. cruzi; but the results have been variable. WHO makes recommendations for prevention and control with the aim of eliminating Chagas disease as a public health problem. Climate change, deforestation, migration, urbanisation, sylvatic vectors and oral transmission require integrating the economic, social, and environmental dimensions of sustainable development, as well as the links within and between objectives and sectors. While the environment scenarios change around the world, native vector species pose a significant public health threat. The man-made atmosphere change is related to the increase of triatomines’ dispersal range, or an increase of the mobility of the vectors from their sylvatic environment to man-made constructions, or humans getting into sylvatic scenarios, leading to an increase of Chagas disease infection. Innovations with the communities and collaborations among municipalities, International cooperation agencies, local governmental agencies, academic partners, developmental agencies, or environmental institutions may present promising solutions, but sustained partnerships, long-term commitment, and strong regional leadership are required. A new world has just opened up for the renewal of surveillance practices, but the lessons learned in the past should be the basis for solutions in the future.
  • The multidimensional comprehension of Chagas disease. Contributions, approaches, challenges and opportunities from and beyond the Information, Education and Communication field Review

    Sanmartino, Mariana; Forsyth, Colin J; Avaria, Andrea; Velarde-Rodriguez, Mar; Gómez i Prat, Jordi; Albajar-Viñas, Pedro

    Abstract in English:

    Chagas is a complex, multidimensional phenomenon in which political, economic, environmental, biomedical, epidemiological, psychological, and sociocultural factors intersect. Nonetheless, the hegemonic conceptualisation has long envisioned Chagas as primarily a biomedical question, while ignoring or downplaying the other dimensions, and this limited view has reinforced the disease’s long neglect. Integrating the multiple dimensions of the problem into a coherent approach adapted to field realities and needs represents an immense challenge, but the payoff is more effective and sustainable experiences, with higher social awareness, increased case detection and follow-up, improved adherence to care, and integrated participation of various actors from multiple action levels. Information, Education, and Communication (IEC) initiatives have great potential for impact in the implementation of multidimensional programs of prevention and control successfully customised to the diverse and complex contexts where Chagas disease persists.
  • Prognosis of chronic Chagas heart disease and other pending clinical challenges Review

    Torres, Rosália Morais; Correia, Dalmo; Nunes, Maria do Carmo Pereira; Dutra, Walderez O; Talvani, André; Sousa, Andréa Silvestre; Mendes, Fernanda de Souza Nogueira Sardinha; Scanavacca, Maurício Ibrahim; Pisani, Cristiano; Moreira, Maria da Consolação Vieira; de Souza, Dilma do Socorro Moraes; de Oliveira Junior, Wilson; Martins, Silvia Marinho; Dias, João Carlos Pinto

    Abstract in English:

    In this chapter, the main prognostic markers of Chagas heart disease are addressed, with an emphasis on the most recent findings and questions, establishing the basis for a broad discussion of recommendations and new approaches to managing Chagas cardiopathy. The main biological and genetic markers and the contribution of the electrocardiogram, echocardiogram and cardiac magnetic resonance are presented. We also discuss the most recent therapeutic proposals for heart failure, thromboembolism and arrhythmias, as well as current experience in heart transplantation in patients suffering from severe Chagas cardiomyopathy. The clinical and epidemiological challenges introduced by acute Chagas disease due to oral contamination are discussed. In addition, we highlight the importance of ageing and comorbidities in influencing the outcome of chronic Chagas heart disease. Finally, we discuss the importance of public policies, the vital role of funding agencies, universities, the scientific community and health professionals, and the application of new technologies in finding solutions for better management of Chagas heart disease.
  • A history of over 40 years of potentially pathogenic free-living amoeba studies in Brazil - a systematic review Review

    Bellini, Natália Karla; Thiemann, Otavio Henrique; Reyes-Batlle, María; Lorenzo-Morales, Jacob; Costa, Adriana Oliveira

    Abstract in English:

    Free-living amoeba (FLA) group includes the potentially pathogenic genera Acanthamoeba, Naegleria, Balamuthia, Sappinia, and Vermamoeba, causative agents of human infections (encephalitis, keratitis, and disseminated diseases). In Brazil, the first report on pathogenic FLA was published in the 70s and showed meningoencephalitis caused by Naegleria spp. FLA studies are emerging, but no literature review is available to investigate this trend in Brazil critically. Thus, the present work aims to integrate and discuss these data. Scopus, PubMed, and Web of Science were searched, retrieving studies from 1974 to 2020. The screening process resulted in 178 papers, which were clustered into core and auxiliary classes and sorted into five categories: wet-bench studies, dry-bench studies, clinical reports, environmental identifications, and literature reviews. The papers dating from the last ten years account for 75% (134/178) of the total publications, indicating the FLA topic has gained Brazilian interest. Moreover, 81% (144/178) address Acanthamoeba-related matter, revealing this genus as the most prevalent in all categories. Brazil’s Southeast, South, and Midwest geographic regions accounted for 96% (171/178) of the publications studied in the present work. To the best of our knowledge, this review is the pioneer in summarising the FLA research history in Brazil.
  • Critical analysis of Chagas disease treatment in different countries Review

    Mendes, Fernanda de Souza Nogueira Sardinha; Perez-Molina, Jose Antonio; Angheben, Andrea; Meymandi, Sheba K; Sosa-Estani, Sergio; Molina, Israel

    Abstract in English:

    As a result of globalization and constant migratory flows, Chagas disease is now present in almost all continents. The management and treatment of the disease is often influenced by the economic and social context of the societies that host patients. In this manuscript, we aim to provide a comparative review of approaches to patients with Chagas disease in the Americas and Europe.
  • Chagas disease control-surveillance in the Americas: the multinational initiatives and the practical impossibility of interrupting vector-borne Trypanosoma cruzi transmission Review

    de Arias, Antonieta Rojas; Monroy, Carlota; Guhl, Felipe; Sosa-Estani, Sergio; Santos, Walter Souza; Abad-Franch, Fernando

    Abstract in English:

    Chagas disease (CD) still imposes a heavy burden on most Latin American countries. Vector-borne and mother-to-child transmission cause several thousand new infections per year, and at least 5 million people carry Trypanosoma cruzi. Access to diagnosis and medical care, however, is far from universal. Starting in the 1990s, CD-endemic countries and the Pan American Health Organization-World Health Organization (PAHO-WHO) launched a series of multinational initiatives for CD control-surveillance. An overview of the initiatives’ aims, achievements, and challenges reveals some key common themes that we discuss here in the context of the WHO 2030 goals for CD. Transmission of T. cruzi via blood transfusion and organ transplantation is effectively under control. T. cruzi, however, is a zoonotic pathogen with 100+ vector species widely spread across the Americas; interrupting vector-borne transmission seems therefore unfeasible. Stronger surveillance systems are, and will continue to be, needed to monitor and control CD. Prevention of vertical transmission demands boosting current efforts to screen pregnant and childbearing-aged women. Finally, integral patient care is a critical unmet need in most countries. The decades-long experience of the initiatives, in sum, hints at the practical impossibility of interrupting vector-borne T. cruzi transmission in the Americas. The concept of disease control seems to provide a more realistic description of what can in effect be achieved by 2030.
  • Population movements, borders, and Chagas disease Review

    Avaria, Andrea; Ventura-Garcia, Laia; Sanmartino, Mariana; Van der Laat, Carlos

    Abstract in English:

    Currently, Chagas disease is a complex global health problem with local and global implications. In the present article, we approach this complexity from the perspective of human mobility and its effects on people’s health in places of origin and in transit and destination. We raise key concepts such as human mobility - understood as a possible socio-structural and economic determination of health -, the associated social and institutional barriers and the processes of social exclusion related to Chagas disease. We also propose what we identify as emerging opportunities from the perspective of health as a right. Finally, we propose strategies aimed at addressing Chagas disease from a multidimensional and intersectional perspective in complex, diverse and interconnected territories through migration.
  • How people affected by Chagas disease have struggled with their negligence: history, associative movement and World Chagas Disease Day Review

    de Oliveira Junior, Wilson Alves; Gómez i Prat, Jordi; Albajar-Viñas, Pedro; Carrazzone, Cristina; Kropf, Simone Petraglia; Dehousse, Aurore; Camargo, Ana Maria de Arruda; Anselmi, Mariella; Barba, Maria Cristina Parada; Guiu, Isabel Claveria; Barros, Maria das Neves Dantas Silveira; Cavalvanti, Maria da Glória Melo; Correia, Cassandra Barros; Martins, Silvia Marinho; FINDECHAGAS Workgroup,

    Abstract in English:

    It is well documented that Chagas disease (CD) can pose a public health problem to countries. As one of the World Health Organization Neglected Tropical Diseases undoubtedly calls for comprehensive healthcare, transcending a restricted biomedical approach. After more than a century since their discovery, in 1909, people affected by CD are still frequently marginalised and/or neglected. The aim of this article is to tell the story of their activism, highlighting key historical experiences and successful initiatives, from 1909 to 2019. The first association was created in 1987, in the city of Recife, Brazil. So far, thirty associations have been reported on five continents. They were created as independent non-profit civil society organisations and run democratically by affected people. Among the common associations’ objectives, we notably find: increase the visibility of the affected; make their voice heard; build bridges between patients, health system professionals, public health officials, policy makers and the academic and scientific communities. The International Federation of Associations of People Affected by CD - FINDECHAGAS, created in 2010 with the input of the Americas, Europe and the Western Pacific, counts as one of the main responses to the globalisation of CD. Despite all the obstacles and difficulties encountered, the Federation has thrived, grown, and matured. As a result of this mobilisation along with the support of many national and international partners, in May 2019 the 72nd World Health Assembly decided to establish World Chagas Disease Day, on 14 April. The associative movement has increased the understanding of the challenges related to the disease and breaks the silence around Chagas disease, improving surveillance, and sustaining engagement towards the United Nations 2030 agenda.
  • Animal models and SARS-CoV-2-induced pulmonary and neurological injuries Review

    Pinto, Marcelo Alves; da Silva, Alexandre dos Santos; Rodrigues, Daniela Del Rosario Flores; Müller, Rodrigo; de Vasconcelos, Gentil Arthur Lins Bentes Mendonça; Neves, Patrícia Cristina da Costa; de Oliveira, Jaqueline Mendes; Marchevsky, Renato Sergio

    Abstract in English:

    Laboratory animals are essential mainly for experiments aiming to study pathogenesis and evaluate antivirals and vaccines against emerging human infectious diseases. Preclinical studies of coronavirus disease 19 (COVID-19) pathogenesis have used several animal species as models: transgenic human ACE2 mice (K18 mice), inbred BALB/c or C57BL/6N mice, ferrets, minks, domestic cats and dogs, hamsters, and macaques. However, the choice of an animal model relies on several limitations. Besides the host susceptibility, the researcher’s experience with animal model management and the correct interpretation of clinical and laboratory records are crucial to succeed in preclinical translational research. Here, we summarise pathological and clinical findings correlated with virological data and immunological changes observed from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experimental infections using different well-established SARS-CoV-2 animal model species. This essay aims to critically evaluate the current state of animal model translation to clinical data, as described in the human SARS-CoV-2 infection.
  • Is the mitochondrion a promising drug target in trypanosomatids? Perspective

    Pedra-Rezende, Yasmin; Bombaça, Ana Cristina Souza; Menna-Barreto, Rubem Figueiredo Sadok

    Abstract in English:

    The trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are etiological agents of important neglected tropical diseases, affecting millions of people worldwide, and the drugs available for these diseases present several limitations. Novel efficient and nontoxic drugs are necessary as an alternative to the current chemotherapy. The unique mitochondrion of trypanosomatids and its peculiar features turn this organelle a potential drug target. Several phenotypic studies describe the damage in the parasite mitochondrial ultrastructure, but the molecular target is unknown. Few reports demonstrated the electron transport system (ETS) as a target due to the high similarities to mammalian orthologues, hence ETS is not a good candidate for drug intervention. On the other hand, antioxidant enzymes, such as trypanothione reductase, and an alternative oxidase (AOX) seem to be interesting targets; however no high active inhibitors were developed up to now. Finally, due to the remarkable differences to mammalian machinery, together with the high biological importance for the parasite survival, the mitochondrial import system stands out as a very promising target in trypanosomatids. Archaic translocase of the outer membrane (ATOM) and translocase of the inner membrane (TIM) complexes, which mediate both protein and tRNA import, composed by specific subunits of these parasites, could be excellent candidates, deserving studies focused on the development of specific drugs.
  • Transforming growth factor-ß as a therapeutic target for the cardiac damage of Chagas disease Perspective

    Waghabi, Mariana Caldas; Ferreira, Roberto Rodrigues; Abreu, Rayane da Silva; Degrave, Wim; de Souza, Elen Mello; Bailly, Sabine; Feige, Jean-Jacques; de Araújo-Jorge, Tania C

    Abstract in English:

    Transforming growth factor beta (TGF-β) is deeply involved on the pathogenesis of Chagas disease. Our group has been investigating the participation of this pleiotropic cytokine in different aspects of Chagas disease over the last 20 years. Important observations have been made, such as: (i) the ability of Trypanosoma cruzi in activating latent TGF-β; (ii) the potential involvement of TGF-β pathway on T. cruzi invasion of host cells; (iii) association of TGF-β with parasite intracellular replication; (iv) cardiac fibrosis development and maintenance; (v) disruption of Connexin-43 plaque structures and (vi) inflammation and immune response. In this perspective article we intend to discuss the advances of the potential use of new therapies targeting TGF-β to treat the cardiac alterations of Chagas disease-affected patients.
  • Antioxidant defence system as a rational target for Chagas disease and Leishmaniasis chemotherapy Perspective

    Santi, Ana Maria Murta; Murta, Silvane Maria Fonseca

    Abstract in English:

    Chagas disease and leishmaniasis are neglected tropical diseases caused by the protozoan parasites Trypanosoma cruzi and Leishmania spp., respectively. They are among the most important parasitic diseases, affecting millions of people worldwide, being a considerable global challenge. However, there is no human vaccine available against T. cruzi and Leishmania infections, and their control is based mainly on chemotherapy. Treatments for Chagas disease and leishmaniasis have multiple limitations, mainly due to the high toxicity of the available drugs, long-term treatment protocols, and the occurrence of drug-resistant parasite strains. In the case of Chagas disease, there is still the problem of low cure rates in the chronic stage of the disease. Therefore, new therapeutic agents and novel targets for drug development are urgently needed. Antioxidant defence in Trypanosomatidae is a potential target for chemotherapy because the organisms present a unique mechanism for trypanothione-dependent detoxification of peroxides, which differs from that found in vertebrates. Cellular thiol redox homeostasis is maintained by the biosynthesis and reduction of trypanothione, involving different enzymes that act in concert. This study provides an overview of the antioxidant defence focusing on iron superoxide dismutase A, tryparedoxin peroxidase, and ascorbate peroxidase and how the enzymes play an important role in the defence against oxidative stress and their involvement in drug resistance mechanisms in T. cruzi and Leishmania spp.
  • Past and future of trypanosomatids high-throughput phenotypic screening Perspective

    Dantas, Rafael Ferreira; Torres-Santos, Eduardo Caio; Silva Jr, Floriano Paes

    Abstract in English:

    Diseases caused by trypanosomatid parasites affect millions of people mainly living in developing countries. Novel drugs are highly needed since there are no vaccines and available treatment has several limitations, such as resistance, low efficacy, and high toxicity. The drug discovery process is often analogous to finding a needle in the haystack. In the last decades a so-called rational drug design paradigm, heavily dependent on computational approaches, has promised to deliver new drugs in a more cost-effective way. Paradoxically however, the mainstay of these computational methods is data-driven, meaning they need activity data for new compounds to be generated and available in databases. Therefore, high-throughput screening (HTS) of compounds still is a much-needed exercise in drug discovery to fuel other rational approaches. In trypanosomatids, due to the scarcity of validated molecular targets and biological complexity of these parasites, phenotypic screening has become an essential tool for the discovery of new bioactive compounds. In this article we discuss the perspectives of phenotypic HTS for trypanosomatid drug discovery with emphasis on the role of image-based, high-content methods. We also propose an ideal cascade of assays for the identification of new drug candidates for clinical development using leishmaniasis as an example.
  • Computational approaches towards the discovery and optimisation of cruzain inhibitors Perspective

    Santos, Viviane Corrêa; Ferreira, Rafaela Salgado

    Abstract in English:

    The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles during the parasite life cycle. Several computational techniques have been applied to discover and optimise cruzain inhibitors, providing a molecular basis to guide this process. Here, we review some of the most recent computational studies that provided important information for the design of cruzain inhibitors. Moreover, we highlight the diversity of applications of in silico techniques and their impact.
  • Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors Perspective

    Sangenito, Leandro Stefano; d’Avila-Levy, Claudia Masini; Branquinha, Marta Helena; Santos, André Luis Souza dos

    Abstract in English:

    Chagas disease (CD) is an old neglected problem that affects more than 6 million people through 21 endemic countries in Latin America. Despite being responsible for more than 12 thousand deaths per year, the disease disposes basically of two drugs for its treatment, the nitroimidazole benznidazole and the nitrofuran nifurtimox. However, these drugs have innumerous limitations that greatly reduce the chances of cure. In Brazil, for example, only benznidazole is available to treat CD patients. Therefore, some proof-of-concept phase II clinical trials focused on improving the current treatment with benznidazole, also comparing it with repositioned drugs or combining them. Indeed, repositioning already marketed drugs in view of combating neglected tropical diseases is a very interesting approach in the context of decreased time for approval, better treatment options and low cost for development and implementation. After the introduction of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) in the treatment of acquired immune deficiency syndrome (AIDS), the prevalence and incidence of parasitic, fungal and bacterial co-infections suffered a marked reduction, making these HIV-PIs attractive for drug repositioning. In this line, the present perspective presents the promising and beneficial data concerning the effects of HIV-PIs on the clinically relevant forms of Trypanosoma cruzi (i.e., trypomastigotes and amastigotes) and also highlights the ultrastructural and physiological targets for the HIV-PIs on this parasite. Therefore, we raise the possibility that HIV-PIs could be considered as alternative treatment options in the struggle against CD.
  • Perspectives for a new drug candidate for Chagas disease therapy Perspective

    Soeiro, Maria de Nazaré Correia

    Abstract in English:

    Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.
  • Antileishmanial metallodrugs and the elucidation of new drug targets linked to post-translational modifications machinery: pitfalls and progress Perspective

    Monte Neto, Rubens Lima do; Moreira, Paulo Otávio Lourenço; de Sousa, Alessandra Mara; Garcia, Miguel Antonio do Nascimento; Maran, Suellen Rodrigues; Moretti, Nilmar Silvio

    Abstract in English:

    Despite the increasing number of manuscripts describing potential alternative antileishmanial compounds, little is advancing on translating these knowledges to new products to treat leishmaniasis. This is in part due to the lack of standardisations during pre-clinical drug discovery stage and also depends on the alignment of goals among universities/research centers, government and pharmaceutical industry. Inspired or not by drug repurposing, metal-based antileishmanial drugs represent a class that deserves more attention on its use for leishmaniasis chemotherapy. Together with new chemical entities, progresses have been made on the knowledge of parasite-specific drug targets specially after using CRISPR/Cas system for functional studies. In this regard, Leishmania parasites undergoe post-translational modification as key regulators in several cellular processes, which represents an entire new field for drug target elucidation, once this is poorly explored. This perspective review describes the advances on antileishmanial metallodrugs and the elucidation of drug targets based on post-translational modifications, highlighting the limitations on the drug discovery/development process and suggesting standardisations focused on products addressed to who need it most.
  • Translational research in Chagas disease: perspectives in nutritional therapy emerging from selenium supplementation studies as a complementary treatment Perspective

    Araujo-Jorge, Tania C de; Ferreira, Roberto R

    Abstract in English:

    Translational research (TR) is an interdisciplinary branch of the biomedical field that seeks to connect its three supporting pillars: basic research on the bench, the hospital beds and other health system services, and the delivery of products for the well-being and health of the community. Here, we review the five transition stages of the TR spectrum, registering the lessons learned during > 20 years leading to the first clinical trial designed and performed in Brazil for testing a complementary treatment for Chagas disease (CD): the selenium trial (STCC). Lessons learned were: (1) to consider all the TR spectrum since the beginning of the project; (2) to start simultaneously animal studies and translation to humans; (3) to ensure a harmonious interaction between clinical and basic research teams; (4) to include MSc and PhD students only in pre-clinical and basic studies (TR0) or vertical clinical studies using retrospective samples and data (TR1); (5) to identify potential suppliers in the national commercial market for a future final treatment since the pre-clinical stage; (6) to keep an international network of experts as permanent advisers on the project. In the whole process, some perspectives were created: a complementary clinical trial for the opened questions and the construction of a Brazilian clinical CD platform.
  • Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach* Perspective

    Lannes-Vieira, Joseli

    Abstract in English:

    Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarise a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling “cytokine storm”. Studies on Chagas’ heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammation-related alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.
  • Proteolytic inhibitors as alternative medicines to treat trypanosomatid-caused diseases: experience with calpain inhibitors Perspective

    Ennes-Vidal, Vítor; dos Santos, André Luis Souza; Branquinha, Marta Helena; d’Avila-Levy, Claudia Masini

    Abstract in English:

    The treatment for tropical neglected diseases, such as Chagas disease (CD) and leishmaniasis, is extremely limited to a handful of drugs that suffer from unacceptable toxicity, tough administration routes, like parenteral, and increasing treatment failures due to the parasite resistance. Consequently, there is urgency for the development of new therapeutic options to treat such diseases. Since peptidases from these parasites are responsible for crucial functions in their biology, these molecules have been explored as alternative targets. In this context, a myriad of proteolytic inhibitors has been developed against calcium-dependent cysteine-type peptidases, collectively called calpains, which are implicated in several human pathophysiological diseases. These molecules are highly expanded in the genome of trypanosomatids and they have been reported participating in several parasite biological processes. In the present perspective, we discuss our almost two decades of experience employing the calpain inhibitors as an interesting shortcut to a possible repurpose strategy to treat CD and leishmaniasis.
  • Natural compounds based chemotherapeutic against Chagas disease and leishmaniasis: mitochondrion as a strategic target Perspective

    Lazarin-Bidóia, Danielle; Garcia, Francielle Pelegrin; Ueda-Nakamura, Tânia; Silva, Sueli de Oliveira; Nakamura, Celso Vataru

    Abstract in English:

    Over the past years, natural products have been explored in order to find biological active substances to treat various diseases. Regarding their potential action against parasites such as trypanosomatids, specially Trypanosoma cruzi and Leishmania spp., much advance has been achieved. Extracts and purified molecules of several species from genera Piper, Tanacetum, Porophyllum, and Copaifera have been widely investigated by our research group and exhibited interesting antitrypanosomal and antileishmanial activities. These natural compounds affected different structures in parasites, and we believe that the mitochondrion is a strategic target to induce parasite death. Considering that these trypanosomatids have a unique mitochondrion, this cellular target has been extensively studied aiming to find more selective drugs, since the current treatment of these neglected tropical diseases has some challenges such as high toxicity and prolonged treatment time. Here, we summarise some results obtained with natural products from our research group and we further highlighted some strategies that must be considered to finally develop an effective chemotherapeutic agent against these parasites.
  • Host cholesterol influences the activity of sterol biosynthesis inhibitors in Leishmania amazonensis Perspective

    Andrade-Neto, Valter Viana; Manso, Pedro Paulo de Abreu; Pereira, Miria Gomes; de Cicco, Nuccia Nicole Theodoro; Atella, Georgia Corrêa; Pelajo-Machado, Marcelo; Menna-Barreto, Rubem Figueiredo Sadok; Torres-Santos, Eduardo Caio

    Abstract in English:

    A significant percentage of exogenous cholesterol was found in promastigotes and amastigotes of all studied species of Leishmania, suggesting a biological role for this molecule. Previous studies have shown that promastigotes of Leishmania uptake more low-density lipoprotein (LDL) particles under pharmacological pressure and are more susceptible to ergosterol inhibition in the absence of exogenous sources of cholesterol. This work shows that the host’s LDL is available to intracellular amastigotes and that the absence of exogenous cholesterol enhances the potency of sterol biosynthesis inhibitors in infected macrophages. A complete understanding of cholesterol transport to the parasitophorous vacuole can guide the development of a new drug class to be used in combination with sterol biosynthesis inhibitors for the treatment of leishmaniases.
  • Article-processing charges as a barrier for science in low-to-medium income regions Perspective

    Rodrigues, Marcio L; Savino, Wilson; Goldenberg, Samuel

    Abstract in English:

    It is widely accepted that science is universal by nature. However, to make science universal, access to research findings is imperative. The open access model of publication of academic articles was established and consolidated during the last two decades. However, most of the open access journals apply article-processing charges (APCs), which can cost more than USD 10,000.00. In regions where support for research is scarce, these funds are usually not available. Similar problems occur in countries with weak economies and, consequently, unfavorable currency conversion rates. This situation reveals a barrier to the alleged universality of science and the access to research findings. In this manuscript, the barriers faced by authors and institutions from low-to-middle income regions to cover APCs and make their science freely available are discussed and illustrated with recent numbers.
  • Family Herpesviridae and neuroinfections: current status and research in progress Perspective

    Carneiro, Vanessa Cristine de Souza; Pereira, Jéssica Gonçalves; de Paula, Vanessa Salete

    Abstract in English:

    This article addresses the relationship between human herpesviruses (HHVs) and neuroinfections. Alphaherpesviruses, betaherpesviruses and gammaherpesviruses are neurotropic viruses that establish latency and exhibit reactivation capacity. Encephalitis and meningitis are common in cases of HHV. The condition promoted by HHV infection is a purported trigger for certain neurodegenerative diseases. Ongoing studies have identified an association between HSV-1 and the occurrence of Alzheimer’s disease, multiple sclerosis and infections by HHV-6 and Epstein-Barr virus. In this review, we highlight the importance of research investigating the role of herpesviruses in the pathogenesis of diseases that affect the nervous system and describe other studies in progress.
  • Genomic surveillance: a potential shortcut for effective Chagas disease management Perspective

    de Azevedo, Sophia Lincoln Cardoso; Catanho, Marcos; Guimarães, Ana Carolina Ramos; Galvão, Teca Calcagno

    Abstract in English:

    Chagas disease is an enduring public health issue in many Latin American countries, receiving insufficient investment in research and development. Strategies for disease control and management currently lack efficient pharmaceuticals, commercial diagnostic kits with improved sensitivity, and vaccines. Genetic heterogeneity of Trypanosoma cruzi is a key aspect for novel drug design since pharmacological technologies rely on the degree of conservation of parasite target proteins. Therefore, there is a need to expand the knowledge regarding parasite genetics which, if fulfilled, could leverage Chagas disease research and development, and improve disease control strategies. The growing capacity of whole-genome sequencing technology and its adoption as disease surveillance routine may be key for solving this long-lasting problem.
  • Mapping Yellow fever epidemics as a potential indicator of the historical range of Aedes aegypti in the United States Research Article

    Fijman, Nicole S; Yee, Donald A

    Abstract in English:

    BACKGROUND Yellow fever (YF) plagued the United States from the 1690s until 1905, resulting in thousands of deaths. Within the US, Aedes aegypti is the only YF vector and almost no data exists for the location of this species prior to the early 1900s. OBJECTIVES To determine the historical range of Ae. aegypti we examined the occurrence of YF epidemics across time and space. We hypothesized that historically Ae. aegypti was driven by human population density, like its contemporary range suggests. METHODS To test this hypothesis, we compiled a list of YF cases in the US, human population density, location, and the number of people infected. This data was mapped using ArcGIS and was analyzed using linear regression models to determine the relationship among variables. FINDINGS The historic range was generally south of 40º latitude, from Texas in the west to Florida in the east, with concentrations along major waterways like the Mississippi River. Infected individuals and human population density were strongly correlated across the whole dataset as well as by decade. MAIN CONCLUSIONS Although other factors likely affected the range of Ae. aegypti, we found that human population density was related to the number of people infected with historic YF infections.
  • Accuracy of rapid point-of-care serological tests for leprosy diagnosis: a systematic review and meta-analysis Research Article

    Romero, Carmen Phang; Castro, Rodolfo; do Brasil, Pedro Emmanuel A; Pereira, Daniella R; Pinheiro, Roberta Olmo; Toscano, Cristiana M; de Oliveira, Maria Regina Fernandes

    Abstract in English:

    BACKGROUND Leprosy is a chronic infectious disease, still endemic in many countries that may lead to neurological, ophthalmic, and motor sequelae if not treated early. Access to timely diagnosis and multidrug therapy (MDT) remains a crucial element in the World Health Organization’s strategy to eliminate the disease as a public health problem. OBJECTIVES This systematic review aims to evaluate the accuracy of rapid point-of-care (POC) tests for diagnosis of leprosy. METHODS Searches were carried out in electronic databases (PubMed, EMBASE, CRD, Cochrane Library and LILACS) in April 2021 for patients with suspicion or confirmatory diagnostic of leprosy, classified in multibacillary (MB) or paucibacillary (PB) cases, performing rapid POC serological tests compared to clinical evaluation, smear microscopy and immunohistochemistry analysis. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). A meta-analysis was undertaken to generate pooled estimates of diagnostic parameters, presenting sensitivity, specificity and diagnostic odds ratio (DOR) values. The review protocol was registered at PROSPERO, CRD # 42014009658. FINDINGS From 893 potentially relevant references, 12 articles were included reporting 16 diagnostic tests accuracy studies with 5395 individuals enrolled. Meta-analysis of NDO-LID and PGL-I tests data in MB patients showed sensitivity and specificity [95% confidence interval (CI)] of 0.83 (0.71-0.91), 0.91 (0.72-0.97); and 0.92 (0.86-0.96), 0.93 (0.78-0.98); respectively, with high heterogeneity among the studies. MAIN CONCLUSIONS Our results can inform policymakers regarding the possibility of implementing accurate, rapid POC tests for leprosy in public health services, especially within primary health care.
  • Callitrichine gammaherpesvirus 3 and Human alphaherpesvirus 1 in New World Primate negative for yellow fever virus in Rio de Janeiro, Brazil Research Article

    Bonfim, Flávia Freitas de Oliveira; Mares-Guia, Maria Angélica Monteiro de Mello; Horta, Marco Aurélio; Chame, Marcia; Lopes, Amanda de Oliveira; Santos, Rafael; Matias, Carlos Alexandre Rey; Pinto, Marcelo Alves; de Filippis, Ana Maria Bispo; de Paula, Vanessa Salete

    Abstract in English:

    BACKGROUND Herpesvirus transmission between humans and non-human primate (NHP) can occur through contact scratches with lesions, infected saliva, and mainly through contaminated food. Therefore, cross-infection can lead to severe illness or even death for both the animal and human. In 2017, during the yellow fever (YF) outbreak in Brazil, species of the New World Primates (NWP) from Rio de Janeiro state, tested negative for yellow fever virus (YFV) detection. OBJECTIVES To evaluate herpesvirus in the population NWP in Rio de Janeiro. METHODS To investigate, liver samples of 283 NWP, from several regions of the state of Rio de Janeiro, were tested for the herpesvirus family using a Pan-polymerase chain reaction (Pan-PCR) and sequencing. FINDINGS 34.6% (98/283) tested positive for at least one herpesvirus; 29.3% (83/283) tested positive to Human alphaherpesvirus 1 (HSV-1), this virus from humans can be lethal to New World monkey; 13% (37/283) were detected Callitrichine gammaherpesvirus 3 (CalHV-3), responsible for lymphoproliferative disease that can be fatal in NWP. In addition, CalHV-3 / HSV-1 co-infection was in 11.6% (33/283) of the samples. MAIN CONCLUSIONS Pan-herpesvirus was useful to identify species-specific herpesviruses and virus from human that can infect animals. Furthermore, during an outbreak of YF other infections should be monitored.
  • Molecular aspects of Chikungunya virus infections in cancer patients Research Article

    Familiar-Macedo, Débora; Gama, Bianca Ervatti; Emmel, Vanessa Erichsen; Vera-Lozada, Gabriela; Abdelhay, Eliana; Martins, Ianick Souto; Hassan, Rocio

    Abstract in English:

    BACKGROUND Chikungunya virus (CHIKV) is an arbovirus that can cause chronic and debilitating manifestations. The first autochthonous case in Rio de Janeiro state was diagnosed in 2015, and an outbreak was declared in 2016. OBJECTIVE The aim of this work was to evaluate CHIKV viral load in serum, plasma and urine in cancer patients to determine the best sample for diagnosis, as well as perform molecular characterisation and phylogenetic analysis of circulating strains. METHODS Paired serum, plasma and urine collected from 31 cancer patients were tested by real-time quantitative polymerase chain reaction (qPCR) and a segment of the CHIKV E1 gene was sequenced. FINDINGS We detected 11 CHIKV+ oncological patients. Paired samples analyses of nine patients showed a different pattern of detection. Also, a higher viral load in plasma (6.84 log10) and serum (6.07 log10) vs urine (3.76 log10) was found. Phylogenetic analysis and molecular characterisation revealed East/Central/Southern Africa (ECSA) genotype circulation and three amino acids substitutions (E1-K211T, E1-M269V, E1-T288I) in positive patients. MAIN CONCLUSION The results indicate the bioequivalence of serum and plasma for CHIKV diagnosis, with urine being an important complement. ECSA genotype was circulating among patients in the period of the 2016 outbreak with K211T, M269V and T288I substitution.
  • Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs Research Article

    El-Jaick, Kenia Balbi; Ribeiro-Alves, Marcelo; Soares, Marcos Vinícius Guimarães; Araujo, Gabriela Eduardo França de; Pereira, Gabriel Rodrigues Coutinho; Rolla, Valeria Cavalcanti; Mesquita, Joelma Freire De; De Castro, Liane

    Abstract in English:

    BACKGROUND Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis. OBJECTIVES This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators. METHODS/FINDINGS The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01]. CONCLUSION These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.
  • Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action Research Article

    Nunes, Débora Cristina de Oliveira Silva; Costa, Mônica Soares; Bispo-da-Silva, Luiz Borges; Ferro, Eloísa Amália Vieira; Zóia, Mariana Alves Pereira; Goulart, Luiz Ricardo; Rodrigues, Renata Santos; Rodrigues, Veridiana de Melo; Yoneyama, Kelly Aparecida Geraldo

    Abstract in English:

    BACKGROUND Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach. In this class of inhibitors is found ketoconazole, a classical inhibitor of 14α-methysterol 14-demethylase. OBJECTIVE The present study aimed to better understand the biological response of Leishmania (Leishmania) amazonensis promastigotes at the cellular level after ketoconazole treatment. METHODS Herein, techniques, such as fluorimetry, flow cytometry, fluorescence microscopy, electron and scanning microscopy were used to investigate the cellular structures and to identify organelles affected by ketoconazole treatment. FINDINGS The study demonstrated, for the first time, the effect of ketoconazole on mitochondrion functioning and its probable relationship to cell cycle and death on L. (L.) amazonensis promastigotes (IFLA/BR/67/PH8 strain). MAIN CONCLUSIONS Ketoconazole-induced mitochondrial damages led to hyperpolarisation of this single organelle and autophagic vacuoles formation, as a parasite survival strategy. These damages did not reflect directly on the parasite cell cycle, but drove the parasites to death, making them susceptible to ketoconazole treatment in in vitro models.
  • First report and genome sequencing of SARS-CoV-2 in a cat (Felis catus) in Colombia Research Article

    Botero, Yesica; Ramírez, Juan David; Serrano-Coll, Héctor; Aleman, Ader; Ballesteros, Nathalia; Martinez, Caty; Muñoz, Marina; Calderon, Alfonso; Patiño, Luz H; Guzman, Camilo; Castañeda, Sergio; Hererra, Yonairo; Mattar, Salim

    Abstract in English:

    BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus of zoonotic origin that can bind to ACE2 receptors on the cells of many wild and domestic mammals. Studies have shown that the virus can circulate among animals mutate, lead to animal-to-human zoonotic jump, and further onward spread between humans. Infection in pets is unusual, and there are few human-to-pet transmission reports worldwide. OBJECTIVE To describe the SARS-CoV-2 infection in a domestic animal in Córdoba, Colombian Caribbean region. METHODS A cross-sectional molecular surveillance study was carried out, oral and rectal swabs were taken from cats and dogs living with people diagnosed with coronavirus disease 2019 (COVID-19). RESULTS SARS-CoV-2 was found in a cat living with a person with COVID-19. Genome sequencing showed that the B.1.111 lineage caused the infection in the cat. The owner’s sample could not be sequenced. The lineage is predominant in Colombia, and this variant is characterised by the presence of the D614D and Q57H mutation. CONCLUSION The present work is the first report of an infected cat with SARS-CoV-2 with whole-genome sequencing in Colombia. It highlights the importance of detecting SARS-CoV-2 mutations that could promote the transmissibility of this new coronavirus. There is still a significant information gap on human-to-cat-to-human infection; we encourage self-isolation measures between COVID-19 patients and companion animals. The findings of this study give a preliminary view of the current panorama of SARS-CoV-2 infection in animals in Colombia.
  • Association of CD209 (DC-SIGN) rs735240 SNV with paucibacillary leprosy in the Brazilian population and its functional effects Research Article

    Germano, Giovanna Valle; Braga, André Flores; Camargo, Rodrigo Mendes de; Ballalai, Priscila Betoni; Bezerra, Ohanna Cavalcanti; Manta, Fernanda Saloum de Neves; Belone, Andréa de Faria Fernandes; Soares, Cleverson Teixeira; Das, Pranab Kumar; Moraes, Milton Ozório; Latini, Ana Carla Pereira; Brito de Souza, Vânia Niéto

    Abstract in English:

    BACKGROUND Leprosy, caused by Mycobacterium leprae, is a public health problem in Brazil that affects peripheral nerves, resulting in physical disabilities. During host-pathogen interactions, the immune response determines leprosy outcomes from a localised (paucibacillary) form to a disseminated (multibacillary) form. The recognition of M. leprae involves the DC-SIGN receptor, which is present on the dendritic cells (DCs) and participates in immune activation. OBJECTIVES To evaluate the association of polymorphisms in the promoter region of the gene encoding DC-SIGN (CD209) and the clinical form of leprosy, and to investigate its functional effects. METHODS The study population included 406 leprosy patients from an endemic area in Brazil [310 multibacillary (MB); 96 paucibacillary (PB)]. A functional evaluation based on the effects of the single nucleotide variant (SNV) associated with PB leprosy on the specific immune response was also performed. RESULTS The GA genotype and the presence of the A allele of rs735240 (-939G>A) were associated with PB leprosy [OR: 2.09 (1.18-3.69) and 1.84 (1.07-3.14), respectively]. Carriers of the A allele showed reduced expression of CD209 and TGF-β1 in leprosy lesions in comparison with individuals with GG genotype, in addition to a higher response to the Mitsuda test. CONCLUSION These data suggest that rs735240 influences the immune response against M. leprae and clinical presentation of leprosy.
  • The scientific publication of the Memórias do Instituto Oswaldo Cruz (1909-2020): a history of contribution to the biomedical sciences Research Article

    Mota, Fabio Batista; Braga, Luiza Amara Maciel; Cabral, Bernardo Pereira; Lopes, Renato Matos; Alves, Luiz Anastácio

    Abstract in English:

    BACKGROUND The Memórias do Instituto Oswaldo Cruz (MIOC) is one of the first scientific journals created in Brazil and currently one of the most important biomedical journals in South America. Knowledge of the main themes disseminated over time and its main contributors can contribute towards a better understanding of its trajectory and future. OBJECTIVES Map the journal’s scientific publication between 1909 and 2020. METHODS Data from three scientific databases was combined, alongside bibliometrics and network analysis to analyse publication records between 1909 and 2020. FINDINGS Publications increased substantially since the 1980s. The main publishing organisations are Brazilian. Excluding Brazil, the main publishing countries are the USA, Argentina, and Colombia. During the entire investigated period, the main themes refer to Chagas disease, schistosomiasis, and Leishmaniasis. During some periods, publications followed disease outbreaks in Brazil (e.g., dengue fever and yellow fever). MAIN CONCLUSIONS Since its foundation in 1909, the MIOC has focused on infectious and parasitic diseases. The editorial changes implemented from the 1980s onwards led MIOC to a relevant growth concerning annual publications and its transformation into an important communication vehicle for researchers from several Brazilian organisations besides Fiocruz, as well as organisations from other countries, especially within Latin America.
  • CCR6 expression reduces mouse survival upon malarial challenge with Plasmodium berghei NK65 strain Research Article

    Silveira, Eduardo Lani Volpe da; Rai, Urvashi; Bonezi, Vivian; Zárate-Bladés, Carlos Rodrigo; Claser, Carla

    Abstract in English:

    BACKGROUND It has been demonstrated that proteins expressed by liver-stage Plasmodium parasites can inhibit the translocation of transcription factors to the nucleus of different cells. This process would hinder the expression of immune genes, such as the CCL20 chemokine. OBJECTIVE Since CCR6 is the only cognate receptor for CCL20, we investigated the importance of this chemokine-receptor axis against rodent malaria. METHODS CCR6-deficient (KO) and wild-type (WT) C57BL/6 mice were challenged with Plasmodium berghei (Pb) NK65 sporozoites or infected red blood cells (iRBCs). Liver parasitic cDNA, parasitemia and serum cytokine concentrations were respectively evaluated through reverse transcription-polymerase chain reaction (RT-PCR), staining thin-blood smears with Giemsa solution, and enzyme-linked immunosorbent assay (ELISA). FINDINGS Although the sporozoite challenges yielded similar liver parasitic cDNA and parasitemia, KO mice presented a prolonged survival than WT mice. After iRBC challenges, KO mice kept displaying higher survival rates as well as a decreased IL-12 p70 concentration in the serum than WT mice. CONCLUSION Our data suggest that malaria triggered by PbNK65 liver- or blood-stage forms elicit a pro-inflammatory environment that culminates with a decreased survival of infected C57BL/6 mice.
  • Binding of the extracellular matrix laminin-1 to Clostridioides difficile strains Research Article

    Santos, Mayara Gil de Castro; Trindade, Camilla Nunes dos Reis; Vommaro, Rossiane Cláudia; Domingues, Regina Maria Calvalcanti Pilotto; Ferreira, Eliane de Oliveira

    Abstract in English:

    BACKGROUND Clostridioides difficile is the most common cause of nosocomial diarrhea associated with antibiotic use. The disease’s symptoms are caused by enterotoxins, but other surface adhesion factors also play a role in the pathogenesis. These adhesins will bind to components of extracellular matrix. OBJECTIVE There is a lack of knowledge on MSCRAMM, this work set-out to determine the adhesive properties of several C. difficile ribotypes (027, 133, 135, 014, 012) towards laminin-1 (LMN-1). METHODS A binding experiment revealed that different ribotypes have distinct adhesion capabilities. To identify this adhesin, an affinity chromatography column containing LMN-1 was prepared and total protein extracts were analysed using mass spectrometry. FINDINGS Strains from ribotypes 012 and 027 had the best adhesion when incubated with glucose supplementations (0.2%, 0.5%, and 1%), while RT135 had a poor adherence. The criteria were not met by RT014 and RT133. In the absence of glucose, there was no adhesion for any ribotype, implying that glucose is required and plays a significant role in adhesion. MAIN CONCLUSIONS These findings show that in the presence of glucose, each C. difficile ribotype interacts differently with LMN-1, and the adhesin responsible for recognition could be SlpA protein.
  • Molecular detection of omicron SARS-CoV-2 variant is achieved by RT-LAMP despite genomic mutations Research Article

    Almeida, Letícia Trindade; Gonçalves, Amanda Bonoto; Franco-Luiz, Ana Paula Moreira; Silva, Thais Bárbara de Souza; Alves, Pedro Augusto; Monte-Neto, Rubens Lima do

    Abstract in English:

    BACKGROUND Severe acute respiratory syndrome coronavirus (SARS-CoV-2) omicron variant was first detected in South Africa in November 2021. Since then, the number of cases due to this variant increases enormously every day in different parts of the world. Mutations within omicron genome may impair the molecular detection resulting in false negative results during Coronavirus disease 19 (COVID-19) diagnosis. OBJECTIVES To verify if colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) targeting N and E genes would work efficiently to detect omicron SARS-CoV-2 variant and its sub-lineages. METHODS SARS-CoV-2 reverse transcription quantitative polymerase chain reaction (RT-qPCR) positive samples were sequenced by next generation DNA sequencing. The consensus sequences generated were submitted to Pangolin tool for SARS-CoV-2 lineage identification. RT-LAMP reactions were performed at 65ºC/30 min targeting N and E. FINDINGS SARS-CoV-2 omicron can be detected by RT-LAMP targeting N and E genes despite the genomic mutation of this more transmissible lineage. Omicron SARS-CoV-2 sub-lineages were tested and efficiently detected by RT-LAMP. We demonstrated that this test is very sensitive in detecting omicron variant, with LoD as low as 0.4 copies/µL. MAIN CONCLUSIONS Molecular detection of omicron SARS-CoV-2 variant and its sub-lineages can be achieved by RT-LAMP despite the genomic mutations as a very sensitive surveillance tool for COVID-19 molecular diagnosis.
  • Prevalence and force of Plasmodium vivax blood-stage infection and associated clinical malaria burden in the Brazilian Amazon Research Article

    Monteiro, Wuelton; Karl, Stephan; Kuehn, Andrea; Almeida, Anne; White, Michael; Vitor-Silva, Sheila; Melo, Gisely; Brito-Sousa, Jose Diego; Baia-da-Silva, Djane Clarys; Silva-Neto, Alexandre Vilhena; Sampaio, Vanderson; Bassat, Quique; Felger, Ingrid; Mueller, Ivo; Lacerda, Marcus

    Abstract in English:

    BACKGROUND Understanding the epidemiology of malaria through the molecular force of the blood-stage infection of Plasmodium vivax (molFOB) may provide a detailed assessment of malaria transmission. OBJECTIVES In this study, we investigated risk factors and spatial-temporal patterns of incidence of Plasmodium infection and clinical malaria episodes in three peri-urban communities of Manaus, Western Brazilian Amazon. METHODS Monthly samples were collected in a cohort of 1,274 individuals between April 2013 and March 2014. DNA samples were subject to Plasmodium species. molFOB was calculated by counting the number of genotypes observed on each visit, which had not been present in the preceding two visits and adjusting these counts by the respective times-at-risk. FINDINGS Respectively, 77.8% and 97.2% of the population remained free of P. vivax and P. falciparum infection. Expected heterozygosity for P. vivax was 0.69 for MSP1_F3 and 0.86 for MS2. Multiplicity of infection in P. vivax was close to the value of 1. The season was associated with P. vivax positivity [adjusted hazard ratio (aHR) 2.6 (1.9-5.7)] and clinical disease [aHR 10.6 (2.4-47.2)]. P. falciparum infection was associated with previous malarial episodes [HR 9.7 (4.5-20.9)]. Subjects who reported possession of a bed net [incidence rate ratio (IRR) 1.6 (1.2-2.2)] or previous malaria episodes [IRR 3.0 (2.0-4.5)] were found to have significantly higher P. vivax molFOB. MAIN CONCLUSIONS Overall, P. vivax infection prevailed in the area and infections were mostly observed as monoclonal. Previous malaria episodes were associated with significantly higher P. vivax molFOB.
  • Chagas disease affects the human placental barrier’s turnover dynamics during pregnancy Research Article

    Mezzano, Luciana; Morán, Joana Paola; Moreira-Espinoza, María José; Triquell, María Fernanda; Mezzano, Julieta; Díaz-Luján, Cintia María; Fretes, Ricardo Emilio

    Abstract in English:

    BACKGROUND Trypanosoma cruzi crosses the placental barrier and produces the congenital transmission of Chagas disease (CD). Structural alterations of the chorionic villi by this parasite have been described in vitro, but little is known about trophoblast turnover in placentas from women with CD. OBJECTIVE To analyze the proliferation and fusion processes in placentas from women with CD. METHODS Archived human term placenta paraffin-embedded blocks were used, from women with CD (CDP), and no pathology (NP). Immunohistochemistry tests were performed for Ki67 to calculate the proliferation index (PI) of cytotrophoblast (CTB) and Syncytin-1, a fusion marker of syncytiotrophoblast (STB). Hematoxylin/Eosin stained sections were employed to analyze STB percentages, STB detachment areas and syncytial knots quantity. Non parametric Student’s t-tests were performed (p < 0.05). RESULTS Syncytial knots and STB detachment significantly increased in placental villi from the CDP group. STB percentage was significantly lower in the CDP group as well as the PI and Syncytin-1 expression significantly decreased in these placentas, compared with control (NP). CONCLUSION Dynamic of trophoblast turnover is altered in placentas from women with CD. These changes may lead into a gap in the placental barrier possibly allowing the parasite entry into the chorionic villi.
  • Toxoplasma gondii in the faeces of wild felids from the Atlantic Forest, Brazil Research Article

    Bolais, Paula F; Galal, Lokman; Cronemberger, Cecília; Pereira, Fabiane de Aguiar; Barbosa, Alynne da Silva; Dib, Laís Verdan; Amendoeira, Maria Regina Reis; Dardé, Marie-Laure; Mercier, Aurélien

    Abstract in English:

    BACKGROUND Toxoplasma gondii is a apicomplexan parasite of virtually all warm-blooded species. All true cats (Felidae) can act as definitive hosts for this parasite by shedding resistant oocysts into the environment. However, the patterns of oocysts shedding are only partially understood in domestic cats and largely unknown in wild felids. OBJECTIVES We carried out molecular analysis of 82 faecal samples from wild felids collected in the Serra dos Órgãos National Park (Parnaso), Rio de Janeiro, Brazil. METHODS We screened samples for T. gondii DNA using a quantitative polymerase chain reaction (qPCR) targeting the 529bp DNA fragment. Polymerase chain reaction (PCR)-positive samples were genotyped using 15 microsatellite markers. RESULTS Only one faecal sample from a Puma yagouaroundi was PCR-positive [cycle threshold (Ct) = 26.88]. This sample was contaminated by a T. gondii strain of BrIII lineage, a common lineage in domestic animals from Brazil. MAIN CONCLUSIONS This first report of T. gondii in faeces of wild South American felids in their natural environment indicates infrequent oocyst shedding and suggests a role of acquired immunity in limiting re-excretion as in domestic cats. The presence of a domestic strain of T. gondii in a faecal sample from a wild felid at very low concentrations (not detected by microscopy) is consistent with the hypothesis of host-parasite co-adaptations limiting the circulation of T. gondii strains between domestic and wild environments.
  • Design of a specific peptide against phenolic glycolipid-1 from Mycobacterium leprae and its implications in leprosy bacilli entry Research Article

    Arenas, Nelson Enrique; Pieffet, Gilles; Rocha-Roa, Cristian; Guerrero, Martha Inírida

    Abstract in English:

    BACKGROUND Mycobacterium leprae, the causative agent of Hansen’s disease, causes neural damage through the specific interaction between the external phenolic glycolipid-1 (PGL-1) and laminin subunit alpha-2 (LAMA2) from Schwann cells. OBJECTIVE To design a LAMA2-based peptide that targets PGL-1 from M. leprae. METHODS We retrieved the protein sequence of human LAMA2 and designed a specific peptide using the Antimicrobial Peptide Database and physicochemical parameters for antimycobacterial peptide-lipid interactions. We used the AlphaFold2 server to predict its three-dimensional structure, AUTODOCK-VINA for docking, and GROMACS programs for molecular dynamics simulations. FINDINGS We analysed 52 candidate peptides from LAMA2, and subsequent screening resulted in a single 60-mer peptide. The mapped peptide comprises four β-sheets and a random coiled region. This peptide exhibits a 45% hydrophobic ratio, in which one-third covers the same surface. Molecular dynamics simulations show that our predicted peptide is stable in aqueous solution and remains stable upon interaction with PGL-1 binding. In addition, we found that PGL-1 has a preference for one of the two faces of the predicted peptide, which could act as the preferential binding site of PGL-1. MAIN CONCLUSIONS Our LAMA2-based peptide targeting PGL-1 might have the potential to specifically block this key molecule, suggesting that the preferential region of the peptide is involved in the initial contact during the attachment of leprosy bacilli to Schwann cells.
  • Suitability of methods for Plasmodium falciparum cultivation in atmospheric air Research Article

    Crispim, Marcell; Verdaguer, Ignasi Bofill; Silva, Sofia Ferreira; Katzin, Alejandro Miguel

    Abstract in English:

    BACKGROUND One of the most controversial factors about malaria parasite culture is the gaseous composition used. The most commonly used one consists of a mixture poor in O2 and rich in CO2. OBJECTIVES The present study aimed to share standard methods from our research group simplifying Plasmodium falciparum cultures by employing atmospheric air (ATM) and reusable glass bottles under agitation. METHODS Here, it was compared the parasite viability, free oxygen in media, and drug sensitivity between different strains and isolates maintained for long periods under ATM or classic conditions. FINDINGS The oxygen concentration in media under ATM was slightly superior to that observed in human blood and the media under the classic gaseous mixture. However, ATM or the use of glass bottles did not affect parasitic proliferation after several years of culture. Noticeably, the introduction of ATM altered reversibly the efficacy of several antimalarials. This influence was different between the strains and isolate. CONCLUSIONS ATM conditions and shaken flasks could be used as a standard method condition for culture manutention since they do not differ greatly from classical 5% O2 gas mixtures in terms of parasite proliferation and do not impose non-reversible changes to P. falciparum physiology.
  • Detection of non-tuberculosus mycobacteria (NTMs) in lung samples using 16S rRNA Research Article

    Morais, Franciele Costa Leite; Bello, Graziele Lima; Costi, Cíntia; Schmid, Karen Barros; Soares, Tainá dos Santos; Barcellos, Regina Bones; Unis, Gisela; Dias, Claudia Fontoura; da Silva, Pedro Eduardo Almeida; Rossetti, Maria Lucia

    Abstract in English:

    BACKGROUND Non-tuberculous mycobacteria (NTMs) cause diseases known as mycobacteriosis and are an important cause of morbidity and mortality. The diagnosis of pulmonary disease caused by NTM is hampered by its clinical similarity with tuberculosis (TB) and by the lack of an accurate and rapid laboratory diagnosis. OBJECTIVES Detect DNA from NTMs directly from lung samples using real-time polymerase chain reaction (qPCR) for amplification of 16S rRNA. Additionally, DNA sequencing (hsp65 and rpoB genes) was used to identify the species of MNTs. METHODS A total of 68 sputum samples (54 with suspected NTMs and 14 with TB) from patients treated at a referral hospital were used. FINDINGS Of these, 27/54 (50%) were qPCR positive for NTMs and 14/14 TB patients (controls) were qPCR negative with an almost perfect concordance (Kappa of 0.93) with the Mycobacterium spp. culture. Sequencing confirmed the presence of NTM in all positive samples. The most common species was Mycobacterium gordonae (33%), followed by Mycobacterium abscessus (26%), Mycobacterium fortuitum (22%), Mycobacterium avium (15%) and Mycobacterium peregrinum (4%). MAIN CONCLUSIONS The qPCR technique for detecting NTMs targeting 16S rRNA has the potential to detect NTMs and rapidly differentiate from Mycobacterium tuberculosis. However, it is necessary to identify the species to help in the differential diagnosis between disease and contamination, and to guide the choice of the therapeutic scheme.
  • Leishmania enriettii visceralises in the trachea, lungs, and spleen of Cavia porcellus Research Article

    Alves-Sobrinho, Ednéia Venâncio; Pinheiro, Lucélia de Jesus; Paranaíba, Larissa Ferreira; Fontes, Igor Campos; Parreiras, Patrícia Martins; Gontijo, Nelder Figueiredo; Tafuri, Wagner Luiz; Laurenti, Márcia Dalastra; Soares, Rodrigo Pedro

    Abstract in English:

    BACKGROUND Leishmania (Mundinia) enriettii is a species commonly found in the guinea pig, Cavia porcellus. Although it is a dermotropic species, there is still an uncertainty regarding its ability to visceralise during Leishmania life cycle. OBJECTIVE Here, we investigated the ability of L. enriettii (strain L88) to visceralise in lungs, trachea, spleen, and liver of C. porcellus, its natural vertebrate host. METHODS Animals were infected sub-cutaneously in the nose and followed for 12 weeks using histological (hematoxilin-eosin) and molecular tools (polymerase chain reaction-restriction fragment length polymorphism - PCR-RFLP). To isolate parasite from C. porcellus, animals were experimentally infected for viscera removal and PCR typing targeting hsp70 gene. FINDINGS Histological analysis revealed intense and diffuse inflammation with the presence of amastigotes in the trachea, lung, and spleen up to 12 weeks post-infection (PI). Molecular analysis of paraffin-embedded tissues detected parasite DNA in the trachea and spleen between the 4th and 8th weeks PI. At the 12th PI, no parasite DNA was detected in any of the organs. To confirm that the spleen could serve as a temporary site for L. enriettii, we performed additional in vivo experiments. During 6th week PI, the parasite was isolated from the spleen confirming previous histopathological and PCR observations. MAIN CONCLUSION Leishmania enriettii (strain L88) was able to visceralise in the trachea, lung, and spleen of C. porcellus.
  • Lack of association of the KIR and HLA class I ligands with ZIKV infection in south and southeast of Brazil Research Article

    Elpidio, Laise Nayana Sala; de Moraes, Amarilis Giaretta; Langer, Ieda Bernadete Volkweis; do Amaral, Greicy Cezar; Moretti, Maria Luiza; Garcia, Márcia Teixeira; Angerami, Rodrigo; Proenca-Modena, José Luiz; Bispo-dos-Santos, Karina; Martini, Matheus Cavalheiro; Parise, Pierina Lorencini; Ayo, Christiane Maria; de Mattos, Luiz Carlos; Brandão, Cinara Cássia; Nogueira, Maurício Lacerda; Oliani, Denise Cristina Mós Vaz; Spegiorin, Lígia Cosentino Junqueira Franco; de Lima Neto, Quirino Alves; Visentainer, Jeane Eliete Laguila

    Abstract in English:

    BACKGROUND Zika virus (ZIKV) is an emerging arbovirus associated with foetal malformations and neurological complications. The infection is usually associated with mild symptoms. The comparison between the allelic frequency of polymorphic genes in symptomatic infected individuals in the population can clarify the pathogenic mechanisms of ZIKV. During ZIKV infection, cytokines are produced and natural killer (NK) cells are recruited, whose activation depends on signaling pathways activated by specific receptors, such as killer cell immunoglobulin-like receptors (KIR). These molecules interact with human leukocyte antigen (HLA) class I ligands and are encoded by polymorphic genes. OBJECTIVES This study aimed to evaluate the frequency of allelic variants of the genes encoding the KIR receptors and their HLA class I ligands in 139 symptomatic ZIKV-patients and 170 controls negative for the virus, and to evaluate the role of these variants for ZIKV susceptibility. METHODS KIR and HLA class I genes were genotyped using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique. FINDINGS No significant differences in the frequency distribution of KIRs and KIR-HLA in patients compared to controls were observed. MAIN CONCLUSIONS KIR and its HLA ligands might play a minor role in ZIKV infection in the south and southeast Brazilian individuals.
  • First report of Leishmania RNA virus 1 in Leishmania (Viannia) braziliensis clinical isolates from Rio de Janeiro State - Brazil Research Article

    Zabala-Peñafiel, Anabel; Fantinatti, Maria; Dias-Lopes, Geovane; da Silva, Jéssica Leite; Miranda, Luciana de Freitas Campos; Lyra, Marcelo Rosandiski; Pimentel, Maria Inês Fernandes; Conceição-Silva, Fátima; Alves, Carlos Roberto

    Abstract in English:

    BACKGROUND Leishmania parasites carry a double-stranded RNA virus (Leishmania RNA virus - LRV) that has been divided in LRV1 and LRV2. OBJECTIVES Leishmania (Viannia) braziliensis clinical isolates were assessed in order to determine LRV presence. METHODS Two-round polymerase chain reaction (PCR and nested PCR) was performed to detect LRV1 or LRV2 in L. (V.) braziliensis clinical isolates (n = 12). FINDINGS LRV1 was detected in three clinical isolates which was phylogenetically related to other sequences reported from other American tegumentary leishmaniasis (ATL) endemic areas of Brazil. Patients infected with L. (V.) braziliensis LRV-negative showed only cutaneous lesions while LRV-positive reported different manifestations. MAIN CONCLUSION Data presented here show for the first time that LRV1 is circulating in L. (V.) braziliensis clinical isolates from Rio de Janeiro State in Brazil.
  • Electrochemical immunosensor for detection of Plasmodium vivax lactate dehydrogenase Research Article

    Gandarilla, Ariamna María Dip; Glória, Juliane Correa; Barcelay, Yonny Romaguera; Mariuba, Luís André Morais; Brito, Walter Ricardo

    Abstract in English:

    BACKGROUND Malaria is a disease that affects many tropical and subtropical countries, including Brazil. The use of tests for malaria detection is one of the fundamental strategies recommended by the World Health Organization for the control and eradication of the disease. The lack of diagnostic tests leads to an increase in transmission and non-reporting cases. OBJECTIVES This work described an electrochemical immunosensor for detecting Plasmodium vivax lactate dehydrogenase antigen (Ag-PvLDH). METHODS The device has developed by immobilising egg yolk IgY antibodies (Ab-PvLDH) on a gold electrode surface using cysteamine as linker. The immunosensor fabrication was followed by differential pulse voltammetry, and contact angle measurements were performed to characterise the modified gold electrode surface. FINDINGS The results for Ag-PvLDH determination exhibit a linear response at 10-50 µg mL-1 concentration range, with a limit of detection of 455 ng mL-1. The excellent selectivity of the device was confirmed. MAIN CONCLUSIONS The developed immunosensor showed a good performance, therefore, it can be considered an alternative test to detect malaria caused by P. vivax.
  • Lack of serological and molecular evidences of Zika virus circulation in non-human primates in three states from Brazil Research Article

    Haisi, Amanda; Wu, Stacy; Zini, Nathalia; da Silva, Maria Luana Cristiny Rodrigues; Malossi, Camila Dantas; Cubas, Zalmir Silvino; Cubas, Patrícia Hoerner; Teixeira, Rodrigo Hidalgo Friciello; de Sousa, Mônica Shinneider; Lucena, Ricardo Barbosa; Svoboda, Walfrido Kühl; Osaki, Silvia Cristina; Nogueira, Mauricio Lacerda; Ullmann, Leila Sabrina; Araújo Junior, João Pessoa

    Abstract in English:

    BACKGROUND Zika virus (ZIKV) was discovered in 1947 with the virus isolation from Rhesus monkey (Macaca mulatta) in Uganda forest, Africa. Old World Primates are involved in a sylvatic cycle of maintenance of this arbovirus, however a limited knowledge about the role of New World primates in ZIKV transmission cycles has been established. OBJECTIVE This work aimed to investigate the presence of enzootic circulation of ZIKV in New World Primates from three Brazilian states: São Paulo, Paraíba, and Paraná. METHODS We analyzed 100 non-human primate samples collected in 2018 and 2020 from free-ranging and captive environments from São Paulo (six municipalities belonging to Sorocaba region), Paraíba (João Pessoa municipality), and Paraná (Foz do Iguaçu municipality) using reverse transcriptase quantitative polymerase reaction (RT-qPCR) assays, indirect enzyme-linked immunosorbent assay (ELISA), and plaque reduction neutralization test (PRNT). FINDINGS All samples (n = 141) tested negative for the presence of ZIKV genome from tissue and blood samples. In addition, all sera (n = 58) from Foz do Iguaçu’ non-human primates (NHPs) were negative in serological assays. MAIN CONCLUSION No evidence of ZIKV circulation (molecular and serological) was found in neotropical primates. In addition, the absence of antibodies against ZIKV suggests the absence of previous viral exposure of NHPs from Foz do Iguaçu-PR.
  • New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole Research Article

    Coelho, Rowena Alves; Alves, Gabriela Machado; Figueiredo-Carvalho, Maria Helena Galdino; Almeida-Silva, Fernando; de Souza, Gabriela Rodrigues; Lourenço, Maria Cristina da Silva; Brito-Santos, Fábio; Amaral, Ana Claudia Fernandes; Almeida-Paes, Rodrigo

    Abstract in English:

    BACKGROUND Black fungi of the Herpotrichiellaceae family are agents of chromoblastomycosis and phaeohyphomycosis. There are few therapeutic options for these infections and it is common to associate antifungal drugs in their treatment. OBJECTIVES To investigate the Medicines for Malaria Venture (MMV) Pathogen Box® for possible compounds presenting synergism with antifungal drugs used to treat black fungal infections. METHODS An initial screening of the Pathogen Box® compounds was performed in combination with itraconazole or terbinafine at sub-inhibitory concentrations against Fonsecaea pedrosoi. Hits were further tested against eight Herpotrichiellaceae using the checkerboard method. FINDINGS No synergism was observed with terbinafine. MMV687273 (SQ109) and MMV688415 showed synergism with itraconazole against F. pedrosoi. Synergism of these compounds was confirmed with some black fungi by the checkerboard method. SQ109 and itraconazole presented synergism for Exophiala dermatitidis, F. pedrosoi, F. monophora and F. nubica, with fungicidal activity for F. pedrosoi and F. monophora. MMV688415 presented synergism with itraconazole only for F. pedrosoi, with fungicidal activity. The synergic compounds had high selectivity index values when combined with itraconazole. MAIN CONCLUSIONS These compounds in combination, particularly SQ109, are promising candidates to treat Fonsecaea spp. and E. dermatitidis infections, which account for most cases of chromoblastomycosis and phaeohyphomycosis.
  • Analysis of a novel class A β-lactamase OKP-B-6 of Klebsiella quasipneumoniae: structural characterisation and interaction with commercially available drugs Research Article

    Bellini, Reinaldo; Guedes, Isabella Alvim; Ciapina, Luciane Prioli; de Vasconcelos, Ana Tereza Ribeiro; Dardenne, Laurent Emmanuel; Nicolás, Marisa Fabiana

    Abstract in English:

    BACKGROUND Gram-negative and Gram-positive bacteria produce beta-lactamase as factors to overcome beta-lactam antibiotics, causing their hydrolysis and impaired antimicrobial action. Class A beta-lactamase contains the chromosomal sulfhydryl reagent variable (SHV, point mutation variants of SHV-1), LEN (Klebsiella pneumoniae strain LEN-1), and other K. pneumoniae beta-lactamase (OKP) found mostly in Klebsiella’s phylogroups. The SHV known as extended-spectrum β-lactamase can inactivate most beta-lactam antibiotics. Class A also includes the worrisome plasmid-encoded Klebsiella pneumoniae carbapenemase (KPC-2), a carbapenemase that can inactivate most beta-lactam antibiotics, carbapenems, and some beta-lactamase inhibitors. OBJECTIVES So far, there is no 3D crystal structure for OKP-B, so our goal was to perform structural characterisation and molecular docking studies of this new enzyme. METHODS We applied a homology modelling method to build the OKP-B-6 structure, which was compared with SHV-1 and KPC-2 according to their electrostatic potentials at the active site. Using the DockThor-VS, we performed molecular docking of the SHV-1 inhibitors commercially available as sulbactam, tazobactam, and avibactam against the constructed model of OKP-B-6. FINDINGS From the point of view of enzyme inhibition, our results indicate that OKP-B-6 should be an extended-spectrum beta-lactamase (ESBL) susceptible to the same drugs as SHV-1. MAIN CONCLUSIONS This conclusion advantageously impacts the clinical control of the bacterial pathogens encoding OKP-B in their genome by using any effective, broad-spectrum, and multitarget inhibitor against SHV-containing bacteria.
  • In vitro activity of Schinus terebinthifolius extract and fractions against Sporothrix brasiliensis Research Article

    Almeida-Silva, Fernando; Bernardes-Engemann, Andrea Reis; Bérenger, Ana Luiza Rangel; da Silva, Vagner Pereira; Figueiredo, Maria Raquel; Freitas, Dayvison Francis Saraiva

    Abstract in English:

    BACKGROUND Sporothrix brasiliensis is the causative agent of zoonotic cases of sporotrichosis in Brazil and is associated with atypical and severe presentations in cats, dogs, and humans. Sporotrichosis treatment is usually time- and cost-consuming, sometimes with poor response and host toxicity. Schinus terebinthifolius has proven efficacy against bacteria and fungi of clinical interest. OBJECTIVE To determine the in vitro activity of S. terebinthifolius against S. brasiliensis. METHODS Five S. brasiliensis isolates and three reference strains were subjected to a hydroethanol extract derived from the leaves of S. terebinthifolius and its fractions. The minimal inhibitory concentration (MIC) was determined using the broth microdilution method according to the M38-A2 CLSI guidelines. Also, the fungicidal/fungistatic activity of the extract and fractions was studied. FINDINGS The crude extract of S. terebinthifolius inhibited the growth of S. brasiliensis (MIC: 0.5-1.0 µg/mL), while the partitioned extracts dichloromethane, ethyl acetate, and butanol demonstrated growth inhibition at 8 µg/mL due to a fungistatic activity. MAIN CONCLUSIONS Due to its in vitro efficacy against S. brasiliensis and its known pharmacological safety, S. terebinthifolius is a candidate to be tested using in vivo models of sporotrichosis.
  • Immunoanalysis of different antigenic preparations of Angiostrongylus cantonensis for neuroangiostrongyliasis diagnosis improvement Research Article

    Melo, Leyva Cecília Vieira de; Souza, Felipe Corrêa Rezende de; Baccin, Amanda de Oliveira; Mota, Dan Jessé Gonçalves da; Pereira-Chioccola, Vera Lucia; Pinto, Pedro Luiz Silva

    Abstract in English:

    BACKGROUND Angiostrongylus cantonensis is the etiological agent of neuroangiostrongyliasis in humans, which is developed in gastropods and vertebrate species, mainly rodents. Human transmission occurs through consumption of molluscs and paratenic hosts infected with L3, and the migration of larvae to the central nervous system causes eosinophilic meningitis. Laboratory diagnosis is based on molecular and immunological tests, using young or adult females as a source of antigens. However, these tests give positive results only after several weeks of symptoms onset and also cross-reactions with others parasite infections may occur. OBJECTIVES The purpose of this work was to study different antigenic preparations of distinct evolutionary phases of A. cantonensis, in order to improve serological techniques for disease immunodiagnosis. METHODS For this purpose, antigenic fractions of different evolutionary forms were evaluated by Dot-enzyme-linked immunosorbent assay (Dot-ELISA) and Western blot using serum samples. FINDINGS All analysed fractions showed reactivity with serum samples from patients with neuroangiostrongyliasis, especially female membrane alkaline (FAM) and female soluble alkaline (FAS) fractions together with female soluble saline (FSS), improving the technique specificity. MAIN CONCLUSIONS The results point to the possibility of use of raw female antigens in association with alkaline membrane antigens extracted from adult worms to aid in diagnosis and helps initiate neuroangiostrongyliasis surveillance and control actions.
  • Characterisation of Neisseria meningitidis cc11/ET-15 variant by whole genome sequencing Research Article

    Santos, Debora Ribeiro de Souza; Bianco, Kayo; Clementino, Maysa Beatriz Mandetta; Dávila, Alberto Martín Rivera; de Filippis, Ivano

    Abstract in English:

    BACKGROUND Neisseria meningitidis strains belonging to clonal complex 11 is the cause of numerous outbreaks and epidemics in the United States, Canada and Europe, accounting for 49.5% of cases of meningococcal disease caused by serogroup C worldwide. In Brazil, it is the second most frequent clonal complex within this serogroup. The genetic characterisation of cc11/ET-15 variants is important for the epidemiological monitoring of meningococcal disease, through the identification of circulating epidemic clones, to support specific actions of Health Surveillance aiming outbreaks control. OBJECTIVES The objective of this study was to identify features in the genome of cc11/ET-15 clones through whole-genome sequencing (WGS), that differ from cc11/non-ET-15 strains that could explain their virulence. METHODS The whole genome of three cc11/ET-15 representative strains were sequenced with a minimum coverage of 100X with the MiSeq System and compared to the genome of cc11/non-ET-15 strains. RESULTS Genome analysis of cc11/ET-15 variants showed the presence of resistance factors, mobile genetic elements and virulence factors not found in cc11/non-ET-15 strains. MAIN CONCLUSIONS Our results show that these strains carry virulence factors not identified in cc11/non-ET-15 strains, which could explain the high lethality rates attributed to this clone worldwide.
  • An updated gene regulatory network reconstruction of multidrug-resistant Pseudomonas aeruginosa CCBH4851 Research Article

    Chagas, Márcia da Silva; Medeiros Filho, Fernando; dos Santos, Marcelo Trindade; de Menezes, Marcio Argollo; Carvalho-Assef, Ana Paula D’Alincourt; Silva, Fabricio Alves Barbosa da

    Abstract in English:

    BACKGROUND Healthcare-associated infections due to multidrug-resistant (MDR) bacteria such as Pseudomonas aeruginosa are significant public health issues worldwide. A system biology approach can help understand bacterial behaviour and provide novel ways to identify potential therapeutic targets and develop new drugs. Gene regulatory networks (GRN) are examples of in silico representation of interaction between regulatory genes and their targets. OBJECTIVES In this work, we update the MDR P. aeruginosa CCBH4851 GRN reconstruction and analyse and discuss its structural properties. METHODS We based this study on the gene orthology inference methodology using the reciprocal best hit method. The P. aeruginosa CCBH4851 genome and GRN, published in 2019, and the P. aeruginosa PAO1 GRN, published in 2020, were used for this update reconstruction process. FINDINGS Our result is a GRN with a greater number of regulatory genes, target genes, and interactions compared to the previous networks, and its structural properties are consistent with the complexity of biological networks and the biological features of P. aeruginosa. MAIN CONCLUSIONS Here, we present the largest and most complete version of P. aeruginosa GRN published to this date, to the best of our knowledge.
  • Heterogeneous persistence of Mycobacterium leprae in oral and nasal mucosa of multibacillary patients during multidrug therapy Research Article

    Neumann, Arthur da Silva; Fontes, Amanda Nogueira Brum; Lopes, Márcia Quinhones Pires; Suffys, Philip Noel; Moraes, Milton Ozório; Lara, Flávio Alves

    Abstract in English:

    BACKGROUND Leprosy is curable by multidrug therapy (MDT) treatment regimen ranging from six to 12 months. The variable levels of tolerance and adherence among patients can, however, result in treatment failure and the emergence of drug-resistant strains. OBJECTIVES Describe the impact of MDT over Mycobacterium leprae viability in patient’s oral and nasal mucosa along treatment. METHODS Mycobacterium leprae viability was monitored by quantitative polymerase chain reaction (qPCR) quantification of 16S rRNA in lateral and contralateral scrapings of oral and nasal mucosa of 10 multibacillary patients along the initial five months of treatment. FINDINGS The results demonstrated high heterogenicity of M. leprae viability among patients and between nasal and oral samples. Of six patients who presented good adherence and tolerance to the treatment, only four displayed absence of M. leprae viability in both samples three months after the first MDT dose, while for the other two, the absence of M. leprae viability in the oral and nasal cavities was only detected five months after the first dose. MAIN CONCLUSIONS We concluded that qPCR of 16S rRNA for the determination of M. leprae viability in nasal and oral scraping samples could represent an interesting approach to monitor treatment efficacy.
  • Genetic diversity of Trypanosoma cruzi strains isolated from chronic chagasic patients and non-human hosts in the state of São Paulo, Brazil Research Article

    Souza, Thiago Kury Moreno de; Westphalen, Elizabeth Visone Nunes; Westphalen, Sansão da Rocha; Taniguchi, Helena Hilomi; Elias, Carlos Roberto; Motoie, Gabriela; Gava, Ricardo; Pereira-Chioccola, Vera Lucia; Novaes, Christina Terra Gallafrio; Carvalho, Noêmia Barbosa; Bocchi, Edimar Alcides; Cruz, Fátima das Dores da; Rocha, Mussya Cisotto; Shinjo, Samuel Katsuyuki; Shikanai-Yasuda, Maria Aparecida; Ortiz, Paola Andrea; Teixeira, Marta Maria Geraldes; Tolezano, José Eduardo

    Abstract in English:

    BACKGROUND Trypanosoma cruzi shows an exuberant genetic diversity. Currently, seven phylogenetic lineages, called discrete typing units (DTUs), are recognised: TcI-TcVI and Tcbat. Despite advances in studies on T. cruzi and its populations, there is no consensus regarding its heterogeneity. OBJECTIVES This study aimed to perform molecular characterisation of T. cruzi strains, isolated in the state of São Paulo, to identify the DTUs involved and evaluate their genetic diversity. METHODS T. cruzi strains were isolated from biological samples of chronic chagasic patients, marsupials and triatomines through culture techniques and subjected to molecular characterisation using the fluorescent fragment length barcoding (FFLB) technique. Subsequently, the results were correlated with complementary information to enable better discrimination between the identified DTUs. FINDINGS It was possible to identify TcI in two humans and two triatomines; TcII/VI in 19 humans, two marsupials and one triatomine; and TcIII in one human host, an individual that also presented a result for TcI, which indicated the possibility of a mixed infection. Regarding the strains characterised by the TcII/VI profile, the correlation with complementary information allowed to suggest that, in general, these parasite populations indeed correspond to the TcII genotype. MAIN CONCLUSIONS The TcII/VI profile, associated with domestic cycles and patients with chronic Chagas disease, was the most prevalent among the identified DTUs. Furthermore, the correlation of the study results with complementary information made it possible to suggest that TcII is the predominant lineage of this work.
  • Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of erythema nodosum leprosum with thalidomide Research Article

    Costa, Perpétua do Socorro Silva; Maciel-Fiuza, Miriãn Ferrão; Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Feira, Mariléa Furtado; Camargo, Luís Marcelo Aranha; Caldoncelli, Daniele Iop de Oliveira; Silveira, Maria Irismar da Silva; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

    Abstract in English:

    BACKGROUND Erythema nodosum leprosum (ENL) is an acute and systemic inflammatory reaction of leprosy characterised by painful nodules and involvement of various organs. Thalidomide is an immunomodulatory and anti-inflammatory drug currently used to treat this condition. Cereblon (CRBN) protein is the primary target of thalidomide, and it has been pointed out as necessary for the efficacy of this drug in others therapeutics settings. OBJECTIVES In this study, we aimed to evaluate the influence of CRBN gene variants on the dose of thalidomide as well as its adverse effects during treatment of ENL. METHODS A total of 103 ENL patients in treatment with thalidomide were included in this study. DNA samples were obtained from saliva and molecular analysis of CRBN gene were performed to investigate the variants rs1620675, rs1672770 and rs4183. Different genotypes of CRBN variants were evaluated in relation to their influence on the dose of thalidomide and on the occurrence of adverse effects. FINDINGS No association was found between CRBN variants and thalidomide dose variation. However, the genotypes of rs1672770 showed association with gastrointestinal effects (p = 0.040). Moreover, the haplotype DEL/C/T (rs4183/rs1672770/rs1620675) was also associated with gastrointestinal adverse effects (p = 0.015). MAIN CONCLUSIONS Our results show that CRBN variants affect the treatment of ENH with thalidomide, especially on the adverse effects related to the drug.
  • COVID-19 outbreaks among crew members in non-cruise vessels anchoring in Salvador, Brazil, 2021 Research Article

    Cardoso, Cristiane Wanderley; Souza, Mirela Maisa da Silva; Teles, Ana Claudia Venegeroles de Sá; Argibay, Hernan Dario; Reis, Olivete Borba dos; Pereira, Felicidade Mota; Giovanetti, Marta; Magalhaes, Tereza; Ribeiro, Guilherme Sousa

    Abstract in English:

    BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected the maritime sector due to virus transmission onboard and traffic restrictions. However, reports of SARS-CoV-2 transmission on board have been mostly restricted to those occurring on cruise ships. OBJECTIVES To report COVID-19 outbreaks in eight non-cruise vessels and discuss measures to prevent and control the onboard transmission of SARS-CoV-2. METHODS We investigated outbreaks of COVID-19 on vessels anchoring in Baía de Todos-os-Santos, Salvador, Brazil, between February and November 2021. FINDINGS Most vessels were cargo ships that had docked several times before anchoring in Salvador (five had docked in ≥ 9 ports). The crew ranged from 22 to 63 members. The infection attack rate on each vessel ranged from 9.7 to 88.9%. The risk of symptomatic infection largely varied among the crew of each vessel (0 to 91.6%). Overall, the risk of developing COVID-19 signs and symptoms was lower among crew members vaccinated (age-adjusted risk ratio: 0.19; 95% confidence interval 0.06-0.65). SARS-CoV-2 variants not previously identified in Salvador were detected (C.14, B.1.617.2 and B.1.351). MAIN CONCLUSIONS Despite maritime guidelines to avert COVID-19 on board, outbreaks have happened. The multiple stopovers of non-cruise vessels during their routes may contribute to the spread of SARS-CoV-2 variants worldwide. Reducing the onboard transmission of SARS-CoV-2 depends on joint efforts by the crew and local health authorities and, equally important, achieving high vaccination coverage to prevent infections and illness.
  • Increased angiogenesis parallels cardiac tissue remodelling in experimental acute Trypanosoma cruzi infection Research Article

    Nisimura, Lindice Mitie; Ferreira, Roberto Rodrigues; Coelho, Laura Lacerda; Souza, Elen Mello de; Gonzaga, Beatriz Matheus; Ferrão, Patrícia Mello; Waghabi, Mariana Caldas; Mesquita, Liliane Batista de; Pereira, Mirian Claudia de Souza; Moreira, Otacilio da Cruz; Lannes-Vieira, Joseli; Garzoni, Luciana Ribeiro

    Abstract in English:

    BACKGROUND Angiogenesis has been implicated in tissue injury in several noninfectious diseases, but its role in Chagas disease (CD) physiopathology is unclear. OBJECTIVES The present study aimed to investigate the effect of Trypanosoma cruzi infection on cardiac angiogenesis during the acute phase of experimental CD. METHODS The signalling pathway involved in blood vessel formation and cardiac remodelling was evaluated in Swiss Webster mice infected with the Y strain of T. cruzi. The levels of molecules involved in the regulation of angiogenesis, such as vascular endothelial growth factor-A (VEGF-A), Flk-1, phosphorylated extracellular-signal-regulated protein kinase (pERK), hypoxia-inducible factor-1α (HIF-1α), CD31, α-smooth muscle actin (α-SMA) and also the blood vessel growth were analysed during T. cruzi infection. Hearts were analysed using conventional histopathology, immunohistochemistry and western blotting. FINDINGS In this study, our data demonstrate that T. cruzi acute infection in mice induces exacerbated angiogenesis in the heart and parallels cardiac remodelling. In comparison with noninfected controls, the cardiac tissue of T. cruzi-infected mice presented higher levels of (i) HIF-1α, VEGF-A, Flk-1 and pERK; (ii) angiogenesis; (iii) α-SMA+ cells in the tissue; and (iv) collagen -1 deposition around blood vessels and infiltrating throughout the myocardium. MAIN CONCLUSIONS We observed cardiac angiogenesis during acute experimental T. cruzi infection parallels cardiac inflammation and remodelling.
  • Fast surveillance response reveals the introduction of a new yellow fever virus sub-lineage in 2021, in Minas Gerais, Brazil Research Article

    Andrade, Miguel Souza; Campos, Fabrício Souza; Oliveira, Cirilo Henrique de; Oliveira, Ramon Silva; Campos, Aline Alves Scarpellini; Almeida, Marco Antônio Barreto de; Fonseca, Vagner de Souza; Simonini-Teixeira, Danilo; Sevá, Anaiá da Paixão; Temponi, Andrea Oliveira Dias; Magalhães, Fernando Maria; Chaves, Danielle Costa Capistrano; Pereira, Maira Alves; Lamounier, Ludmila Oliveira; Menezes, Givaldo Gomes de; Aquino-Teixeira, Sandy Micaele; Gonçalves-dos-Santos, Maria Eduarda; Bernal-Valle, Sofía; Müller, Nicolas Felipe Drumm; Cardoso, Jader da Cruz; Santos, Edmilson dos; Mares-Guia, Maria Angélica; Albuquerque, George Rêgo; Romano, Alessandro Pecego Martins; Franco, Ana Cláudia; Ribeiro, Bergmann Morais; Roehe, Paulo Michel; Abreu, Filipe Vieira Santos de

    Abstract in English:

    BACKGROUND In Brazil, the yellow fever virus (YFV) is maintained in a sylvatic cycle involving wild mosquitoes and non-human primates (NHPs). The virus is endemic to the Amazon region; however, waves of epidemic expansion reaching other Brazilian states sporadically occur, eventually causing spillovers to humans. OBJECTIVES To report a surveillance effort that led to the first confirmation of YFV in NHPs in the state of Minas Gerais (MG), Southeast region, in 2021. METHODS A surveillance network was created, encompassing the technology of smartphone applications and coordinated actions of several research institutions and health services to monitor and investigate NHP epizootics. FINDINGS When alerts were spread through the network, samples from NHPs were collected and YFV infection confirmed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and genome sequencing at an interval of only 10 days. Near-complete genomes were generated using the Nanopore MinION sequencer. Phylogenetic analysis indicated that viral genomes were related to the South American genotype I, clustering with a genome detected in the Amazon region (state of Pará) in 2017, named YFVPA/MG sub-lineage. Fast YFV confirmation potentialised vaccination campaigns. MAIN CONCLUSIONS A new YFV introduction was detected in MG 6 years after the beginning of the major outbreak reported in the state (2015-2018). The YFV strain was not related to the sub-lineages previously reported in MG. No human cases have been reported, suggesting the importance of coordinated surveillance of NHPs using available technologies and supporting laboratories to ensure a quick response and implementation of contingency measures to avoid YFV spillover to humans.
  • Clinically silent Plasmodium vivax infections in native Amazonians of northwestern Brazil: acquired immunity or low parasite virulence? Research Article

    Barros, Luiza Barbosa; Calil, Priscila Rodrigues; Rodrigues, Priscila Thihara; Tonini, Juliana; Fontoura, Pablo Secato; Sato, Priscila Moraes; Cardoso, Marly Augusto; Russo, Marina Werneck de Almeida Avellar; Cavasini, Carlos Eduardo; Fernandes, Anderson Rocha de Jesus; Ferreira, Marcelo Urbano

    Abstract in English:

    BACKGROUND Malaria remains common among native Amazonians, challenging Brazil′s elimination efforts. OBJECTIVES We examined the epidemiology of malaria in riverine populations of the country′s main hotspot - the upper Juruá Valley in Acre state, close to the Brazil-Peru border, where Plasmodium vivax accounts for > 80% of cases. METHODS Participants (n = 262) from 10 villages along the Azul River were screened for malaria parasites by microscopy and genus-specific, cytochrome b (cytb) gene-based polymerase chain reaction. Positive samples were further tested with quantitative TaqMan assays targeting P. vivax- and P. falciparum-specific cytb domains. We used multiple logistic regression analysis to identify independent correlates of P. vivax infection. FINDINGS Microscopy detected only one P. vivax and two P. falciparum infections. TaqMan assays detected 33 P. vivax infections (prevalence, 11.1%), 78.1% of which asymptomatic, with a median parasitaemia of 34/mL. Increasing age, male sex and use of insecticide-treated bed nets were significant predictors of elevated P. vivax malaria risk. Children and adults were similarly likely to remain asymptomatic once infected. MAIN CONCLUSIONS Our findings are at odds with the hypothesis of age-related clinical immunity in native Amazonians. The low virulence of local parasites is suggested as an alternative explanation for subclinical infections in isolated populations.
  • Detection and genome characterisation of SARS-CoV-2 P.6 lineage in dogs and cats living with Uruguayan COVID-19 patients Research Article

    Panzera, Yanina; Mirazo, Santiago; Baz, Mariana; Techera, Claudia; Grecco, Sofía; Cancela, Florencia; Fuques, Eddie; Condon, Emma; Calleros, Lucía; Camilo, Natalia; Fregossi, Andrea; Vaz, Inés; Pessina, Paula; Deshpande, Nikita; Pérez, Ruben; Benech, Alejandro

    Abstract in English:

    BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in domestic animals have occurred from the beginning of the pandemic to the present time. Therefore, from the perspective of One Health, investigating this topic is of global scientific and public interest. OBJECTIVES The present study aimed to determine the presence of SARS-CoV-2 in domestic animals whose owners had coronavirus disease 2019 (COVID-19). METHODS Nasopharyngeal and faecal samples were collected in Uruguay. Using quantitative polymerase chain reaction (qPCR), we analysed the presence of the SARS-CoV-2 genome. Complete genomes were obtained using ARTIC enrichment and Illumina sequencing. Sera samples were used for virus neutralisation assays. FINDINGS SARS-CoV-2 was detected in an asymptomatic dog and a cat. Viral genomes were identical and belonged to the P.6 Uruguayan SARS-CoV-2 lineage. Only antiserum from the infected cat contained neutralising antibodies against the ancestral SARS-CoV-2 strain and showed cross-reactivity against the Delta but not against the B.A.1 Omicron variant. MAIN CONCLUSIONS Domestic animals and the human SARS-CoV-2 P.6 variant comparison evidence a close relationship and gene flow between them. Different SARS-CoV-2 lineages infect dogs and cats, and no specific variants are adapted to domestic animals. This first record of SARS-CoV-2 in domestic animals from Uruguay supports regular surveillance of animals close to human hosts.
  • Raising the suspicion of a non-autochthonous infection: identification of Leishmania guyanensis from Costa Rica exhibits a Leishmaniavirus related to Brazilian north-east and French Guiana viral genotypes Research Article

    Mata-Somarribas, Carlos; Quesada-López, José; Matamoros, María F; Cervantes-Gómez, César; Mejía, Annia; Chacón, Karen; Bendig, Ivannia; Campos, Roger; Quesada-Morera, Raphael; Cantanhêde, Lilian Motta; Pereira, Luiza de Oliveira R; Cupolillo, Elisa

    Abstract in English:

    BACKGROUND Costa Rica has a history of neglecting prevention, control and research of leishmaniasis, including limited understanding on Leishmania species causing human disease across the country and a complete lack of knowledge on the Leishmania RNA virus, described as a factor linked to the worsening and metastasis of leishmanial lesions. OBJECTIVES The aim of this work was to describe a case of cutaneous leishmaniasis by Leishmania (Viannia) guyanensis, bearing infection with Leishmaniavirus 1 (LRV1) in Costa Rica, raising the suspicion of imported parasites in the region. METHODS The Leishmania strain was previously identified by routine hsp70 polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in Costa Rica and subsequently characterised by isoenzyme electrophoresis and Sanger sequencing in Brazil. Screening for LRV1 was conducted with a dual RT-PCR approach and sequencing of the fragment obtained. FINDINGS Since 2016 Costa Rica performs Leishmania isolation and typing as part of its epidemiological surveillance activities. Amongst 113 strains typed until 2019, only one was characterised as a L. (V.) guyanensis, corresponding to the first confirmed report of this species in the country. Interestingly, the same strain tested positive for LRV1. Sequencing of the viral orf1 and 2, clustered this sample with other LRV1 genotypes of South American origin, from the Northeast of Brazil and French Guiana. MAIN CONCLUSION The unique characteristics of this finding raised the suspicion that it was not an autochthonous strain. Notwithstanding its presumed origin, this report points to the occurrence of said endosymbiont in Central American Leishmania strains. The possibility of its local dispersion represents one more challenge faced by regional health authorities in preventing and controlling leishmaniasis.
  • Progressive neuropathy in patients with lepromatous leprosy after multidrug therapy Research Article

    Penna, Patricia Sola; Pitta, Izabela Jardim Rodrigues; Vital, Robson Teixeira; Hacker, Mariana Andrea Vilas Boas; Salles, Ana Maria; Pinheiro, Roberta Olmo; Antunes, Sergio Luiz Gomes; Sarno, Euzenir Nunes; Jardim, Márcia Rodrigues

    Abstract in English:

    BACKGROUND The lepromatous pole is a stigmatising prototype for patients with leprosy. Generally, these patients have little or no symptoms of peripheral nerve involvement at the time of their diagnosis. However, signs of advanced peripheral neuropathy would be visible during the initial neurological evaluation and could worsen during and after multidrug therapy (MDT). Disabilities caused by peripheral nerve injuries greatly affect these patients’ lives, and the pathophysiological mechanisms underlying nerve damage remain unclear. OBJECTIVES To evaluate the outcome of peripheral neuropathy in patients with lepromatous leprosy (LL) and persistent neuropathic symptoms years after completing MDT. METHODS We evaluated the medical records of 14 patients with LL who underwent nerve biopsies due to worsening neuropathy at least four years after MDT. FINDINGS Neuropathic pain developed in 64.3% of the patients, and a neurological examination showed that most patients had alterations in the medium- and large-caliber fibers at the beginning of treatment. Neurological symptoms and signs deteriorated despite complete MDT and prednisone or thalidomide use for years. Nerve conduction studies showed that sensory nerves were the most affected. MAIN CONCLUSIONS Patients with LL can develop progressive peripheral neuropathy, which continues to develop even when they are on long-term anti-inflammatory and immunosuppressive therapy.
  • Clinical and epidemiological aspects of Delta and Gamma SARS-CoV-2 variant of concern from the western Brazilian Amazon Research Article

    Sgorlon, Gabriella; Queiroz, Jackson Alves da Silva; Roca, Tárcio Peixoto; Silva, Ana Maisa Passos da; Gasparelo, Nadson Willian Felipe; Teixeira, Karolaine Santos; Oliveira, Andreia Souza da Nóbrega; Mendonça, Aline Linhares Ferreira de Melo; Maia, Adriana Cristina Salvador; Pereira, Soraya dos Santos; Batista, Flávia Serrano; Salcedo, Juan Miguel Villalobos; Rampazzo, Rita de Cassia Pontello; Resende, Paola Cristina; Siqueira, Marilda Mendonça; Naveca, Felipe Gomes; Vieira, Deusilene

    Abstract in English:

    BACKGROUND The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has become a major concern contributing to increased morbidity and mortality worldwide. OBJECTIVES Here we describe the replacement of the Gamma variant of concern (VOC) with Delta in the western Brazilian Amazon. METHODS In this study, we analysed 540 SARS-CoV-2 positive samples determined by qualitative real-time RT-PCR selected in the state of Rondônia between June and December 2021. The positive cohort was sequenced through next-generation sequencing (NGS) and each sample was quantified using real-time RT-qPCR, the whole genome sequence was obtained, SARS-CoV-2 lineages were classified using the system Pango and the maximum likelihood (ML) method was used to conduct phylogenetic analyses. FINDINGS A total of 540 high-quality genomes were obtained, where the Delta VOC showed the highest prevalence making up 72%, with strain AY.43 being the most abundant, while the Gamma VOC was present in 28%, where the P.1 strain was the most frequent. In this study population, only 32.96% (178/540) had completed the vaccination schedule. MAIN CONCLUSIONS This study highlighted the presence of Gamma and Delta variants of SARS-CoV-2 in RO. Furthermore, we observed the replacement of the Gamma VOC with the Delta VOC and its lineages.
  • Coagulopathy and the humoral response against viral proteins in patients at different stages of COVID-19 Research Article

    Monteiro, Fernanda Pereira; Tavares, Victor de Souza; Souza, Rayane da Silva Oliveira; Venâncio, Larissa Paola Rodrigues; Fabres-Klein, Mary Hellen; do Carmo, Rodrigo Feliciano; Klein, Raphael Contelli; Lima, Jonilson Berlink; Araújo-Santos, Théo

    Abstract in English:

    BACKGROUND Patients with severe coronavirus disease 2019 (COVID-19) often present with coagulopathies and have high titres of circulating antibodies against viral proteins. OBJECTIVES Herein, we evaluated the association between D-dimer and circulating immunoglobulin levels against viral proteins in patients at different clinical stages of COVID-19. METHODS For this, we performed a cross-sectional study involving patients of the first wave of COVID-19 clinically classified as oligosymptomatic (n = 22), severe (n = 30), cured (n = 27) and non-infected (n = 9). Next, we measured in the plasma samples the total and fraction of immunoglobulins against the nucleoprotein (NP) and the receptor-binding domain (RBD) of the spike proteins by enzyme-linked immunosorbent assay (ELISA) assays. FINDINGS Patients with severe disease had a coagulation disorder with high levels of D-dimer as well as circulating IgG against the NP but not the RBD compared to other groups of patients. In addition, high levels of D-dimer and IgG against the NP and RBD were associated with disease severity among the patients in this study. MAIN CONCLUSIONS Our data suggest that IgG against NP and RBD participates in the worsening of COVID-19. Although the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is partially understood, and more efforts are needed to clarify gaps in the knowledge of this process.
  • Tracing the relationship among HIV-1 sub-subtype F1 strains: a phylodynamic perspective Research Article

    Silva, Gabriela Porto Santos Almeida; Oliveira, Rodrigo Cunha; de Souza, Juliana Sacramento Mota; Giovanetti, Marta; Guimarães, Monick Lindenmeyer; Brites, Carlos; Monteiro-Cunha, Joana Paixão

    Abstract in English:

    BACKGROUND The human immunodeficiency virus type 1, F1 sub-subtype (HIV-1 F1) circulates in three continents: Africa, Europe, and South America. In Brazil, this sub-subtype co-circulates with subtypes B and C and several recombinant forms, mainly BF1 variants. OBJECTIVES This study aimed to reconstruct the dynamic history of HIV-1 F1 in Brazil. METHODS HIV-1 near full-length genome and pol gene nucleotide sequences available in public databases were assembled in two datasets (POL671 and NFLG53) to cover the largest number of F1 sub-subtype sequences. Phylodynamic and temporal analyses were performed. FINDINGS Two main strains of the F1 sub-subtype are circulating worldwide. The first (F1.I) was found among Brazilian samples (75%) and the second (F1.II) among Romanian (62%) and other European and African isolates. The F1 subtype epidemic in Brazil originated from a single entry into the country around 1970. This ancestral sample is related to samples isolated in European countries (France, Finland, and Belgium), which are possibly of African origin. Moreover, further migration (1998 CI: 1994-2003) of strains from Brazil to Europe (Spain and the UK) was observed. Interestingly, all different recombinant BF patterns found, even those from outside Brazil, present the same F1 lineage (F1.I) as an ancestor, which could be related to the acquisition of adaptive advantages for the recombinant progenies. MAIN CONCLUSIONS These findings are important for the understanding of the origin and dynamics of the F1 sub-subtype and a consequent better and greater understanding of the HIV-1 F1 and BF epidemic that still spreads from Brazil to other countries.
  • Intravenous whole blood transfusion results in faster recovery of vascular integrity and increased survival in experimental cerebral malaria Research Article

    Gul, Saba; Ackerman, Hans C; Daniel-Ribeiro, Cláudio Tadeu; Carvalho, Leonardo JM

    Abstract in English:

    BACKGROUND Cerebral malaria is a lethal complication of Plasmodium falciparum infections in need of better therapies. Previous work in murine experimental cerebral malaria (ECM) indicated that the combination of artemether plus intraperitoneal whole blood improved vascular integrity and increased survival compared to artemether alone. However, the effects of blood or plasma transfusion administered via the intravenous route have not previously been evaluated in ECM. OBJECTIVES To evaluate the effects of intravenous whole blood compared to intravenous plasma on hematological parameters, vascular integrity, and survival in artemether-treated ECM. METHODS Mice with late-stage ECM received artemether alone or in combination with whole blood or plasma administered via the jugular vein. The outcome measures were hematocrit and platelets; plasma angiopoietin 1, angiopoietin 2, and haptoglobin; blood-brain barrier permeability; and survival. FINDINGS Survival increased from 54% with artemether alone to 90% with the combination of artemether and intravenous whole blood. Intravenous plasma lowered survival to 18%. Intravenous transfusion provided fast and pronounced recoveries of hematocrit, platelets, angiopoietins levels and blood brain barrier integrity. MAIN CONCLUSIONS The outcome of artemether-treated ECM was improved by intravenous whole blood but worsened by intravenous plasma. Compared to prior studies of transfusion via the intraperitoneal route, intravenous administration was more efficacious.
  • Morel paper is a passionate plea for the concept of “translation” with translational research (TR) as a flag Article Commentary

    Jannin, Jean
  • Waiting for a success story in prevention, control and treatment of Chagas disease in non-endemic countries Article Commentary

    Bartoloni, Alessandro
  • Peeking into the mysterious world of Trypanosoma cruzi and Chagas disease Article Commentary

    Macedo, Andréa M; Pena, Sérgio DJ
  • Trypanosoma cruzi and Chagas disease: diversity, progress and challenges Article Commentary

    Miles, Michael A
  • A safe, effective, and reliable vaccine against Chagas disease should be described! Article Commentary

    Silva, João S
  • Brazilian immunology in Caxambu: beyond vaccination, a tribute to the pioneers of basic research in Chagas disease Article Commentary

    Scharfstein, Julio
  • The challenges for targeting Chagas disease for elimination as a public health problem Article Commentary

    Werneck, Guilherme Loureiro
  • Chagas disease challenge - New techniques for diagnosis and treatment address to control in endemic areas Article Commentary

    Marins, José Ricardo Pio
  • Chagas disease and its historicity Article Commentary

    Gomes, Ana Carolina Vimieiro
  • A note on the the discovery of Chagas' disease Article Commentary

    de Avila-Pires, Fernando Dias
  • Reflections on Chagas disease in the Amazon Article Commentary

    Aguilar, V H Marcelo
  • Challenges for fighting Chagas disease in the 21st century Article Commentary

    Freitas, Laís Picinini; Lana, Raquel Martins; Cruz, Oswaldo Gonçalves
  • Chagas disease treatment: a 120-year-old challenge to public health Article Commentary

    Goldenberg, Samuel
  • Comment on “The translational challenge in Chagas disease drug development” by Kratz et al. Article Commentary

    De Rycker, Manu
  • Air in the tires: towards an achievable, efficacious and timely diagnosis for Chagas disease Article Commentary

    Angheben, Andrea
  • Revisiting Chagas' disease diagnostic strategies in light of different scenarios of Trypanosoma cruzi infection Article Commentary

    Britto, Constança Carvalho
  • How is global change affecting Chagas disease landscapes? Article Commentary

    Gürtler, Ricardo E
  • Chagas disease (American trypanosomiasis) in the context of the 2030 agenda. Insights into global warming and vector control Article Commentary

    Jurberg, José
  • Reflections how IEC can empower and integrate stakeholders to denormalise Chagas disease and drive care and prevention policy: healthcare system governance at the heart of Chagas disease neglect Article Commentary

    Ramsey, Janine M
  • Reflections, suggestions for putting into practice the principles of information, education and communication - IEC on Chagas disease in a community context Article Commentary

    Anselmi, Mariella
  • Pathophysiology and new targets for therapeutic options in Chagas heart disease Article Commentary

    Ferreira, João Marcos B Barbosa
  • The challenge of risk assessment in the riddle of Chagas heart disease Article Commentary

    Marin-Neto, José Antonio; Rassi Jr, Anis
  • Traditional use of benznidazole with weekly clinical follow-up indicate to be an important approach for the etiologic treatment of Chagas disease Article Commentary

    Sperandio da Silva, Gilberto Marcelo
  • Subregional initiatives for Chagas disease. A path of technical cooperation, opened by the countries, as an approach to a neglected disease Article Commentary

    Lima, José Fiusa
  • Chagas disease and mobility: comments on the challenges for access and the right to health for migrants Article Commentary

    Peiter, Paulo Cesar
  • The achievement of a storytelling about Chagas disease: how to talk about silence; how to visualise the invisible Article Commentary

    Sancho Mas, Francisco Javier
  • A glimmer of hope for a neglected disease - How Chagas disease associative movement is driving progress towards disease control and elimination Article Commentary

    Batista, Carolina
  • Stronger control-surveillance systems for vector-borne Chagas disease Article Commentary

    Gurgel-Gonçalves, Rodrigo
Instituto Oswaldo Cruz, Ministério da Saúde Av. Brasil, 4365 - Pavilhão Mourisco, Manguinhos, 21040-900 Rio de Janeiro RJ Brazil, Tel.: (55 21) 2562-1222, Fax: (55 21) 2562 1220 - Rio de Janeiro - RJ - Brazil