Resumo em Inglês:

In Cryptococcus neoformans, nearly all genes are interrupted by small introns. In recent years, genome annotation and genetic analysis have illuminated the major roles these introns play in the biology of this pathogenic yeast. Introns are necessary for gene expression and alternative splicing can regulate gene expression in response to environmental cues. In addition, recent studies have revealed that C. neoformans introns help to prevent transposon dissemination and protect genome integrity. These characteristics of cryptococcal introns are probably not unique to Cryptococcus, and this yeast likely can be considered as a model for intron-related studies in fungi.

Resumo em Inglês:

Cryptococcus species are the causative agents of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals. Initial work on the molecular epidemiology of this fungal pathogen utilized genotyping approaches to describe the genetic diversity and biogeography of two species, Cryptococcus neoformans and Cryptococcus gattii. Whole genome sequencing of representatives of both species resulted in reference assemblies enabling a wide array of downstream studies and genomic resources. With the increasing availability of whole genome sequencing, both species have now had hundreds of individual isolates sequenced, providing fine-scale insight into the evolution and diversification of Cryptococcus and allowing for the first genome-wide association studies to identify genetic variants associated with human virulence. Sequencing has also begun to examine the microevolution of isolates during prolonged infection and to identify variants specific to outbreak lineages, highlighting the potential role of hyper-mutation in evolving within short time scales. We can anticipate that further advances in sequencing technology and sequencing microbial genomes at scale, including metagenomics approaches, will continue to refine our view of how the evolution of Cryptococcus drives its success as a pathogen.

Resumo em Inglês:

Cryptococcal meningitis is the most common central nervous system infection in the world today. It occurs primarily, but not exclusively, in immunocompromised individuals and despite substantial improvement in management of clinical events like AIDS, the numbers of cases of cryptococcosis remain very high. Unfortunately, despite several antifungal agents available for treatment, morbidity and mortality rates remain high with this fungal infection. In this Review, we will describe the treatments and strategies for success, identify the failures, and provide insights into the future developments / improvements for management. This sugar-coated yeast can play havoc within the human brain. Our goals must be to either prevent or diagnose disease early and treat aggressively with all our clinical tools when disease is detected.

Resumo em Inglês:

Cryptococcosis is a life-threatening fungal infection caused by the encapsulated yeasts Cryptococcus neoformans and C. gattii, acquired from the environment. In Latin America, as occurring worldwide, C. neoformans causes more than 90% of the cases of cryptococcosis, affecting predominantly patients with HIV, while C. gattii generally affects otherwise healthy individuals. In this region, cryptococcal meningitis is the most common presentation, with amphotericin B and fluconazole being the antifungal drugs of choice. Avian droppings are the predominant environmental reservoir of C. neoformans, while C. gattii is associated with several arboreal species. Importantly, C. gattii has a high prevalence in Latin America and has been proposed to be the likely origin of some C. gattii populations in North America. Thus, in the recent years, significant progress has been made with the study of the basic biology and laboratory identification of cryptococcal strains, in understanding their ecology, population genetics, host-pathogen interactions, and the clinical epidemiology of this important mycosis in Latin America.

Resumo em Inglês:

Cryptococcus neoformans is an opportunistic pathogenic yeast that causes serious infections, most commonly of the central nervous system (CNS). C. neoformans is mainly found in the environment and acquired by inhalation. It could be metaphorically imagined that cryptococcal disease is a “journey” for the microorganism that starts in the environment, where this yeast loads its suitcase with virulence traits. C. neoformans first encounters the infected mammalian host in the lungs, a site in which it must choose the right elements from its “virulence suitcase” to survive the pulmonary immune response. However, the lung is often only the first stop in this journey, and in some individuals the fungal trip continues to the brain. To enter the brain, C. neoformans must “open” the main barrier that protects this organ, the blood brain barrier (BBB). Once in the brain, C. neoformans expresses a distinct set of protective attributes that confers a strong neurotropism and the ability to cause brain colonisation. In summary, C. neoformans is a unique fungal pathogen as shown in its ability to survive in the face of multiple stress factors and to express virulence factors that contribute to the development of disease.

Resumo em Inglês:

Cryptococcosis is an invasive fungal disease caused by Cryptococcus neoformans and the closely related species C. gattii. The severe form of the disease, cryptococcal meningitis (CM), is rapidly fatal without treatment. Although typically a disease of immunocompromised (especially HIV-positive) individuals, there is growing awareness of cryptococcal disease amongst non-immunocompromised patients. Whilst substantial progress has been made in understanding the pathogenicity of C. neoformans in HIV patients, prospective data on cryptococcosis outside the context of HIV remains lacking. Below we review how innate immune responses vary between hosts depending on immunological status, and discuss risk factors and predictors of disease outcome in different groups.

Resumo em Inglês:

Cryptococcus neoformans is an opportunistic fungal pathogen that is ubiquitous in the environment. It causes a deadly meningitis that is responsible for over 180,000 deaths worldwide each year, including 15% of all AIDS-related deaths. The high mortality rates for this infection, even with treatment, suggest a need for improved therapy. Unique characteristics of C. neoformans may suggest directions for drug discovery. These include features of three structures that surround the cell: the plasma membrane, the cell wall around it, and the outermost polysaccharide capsule. We review current knowledge of the fundamental biology of these fascinating structures and highlight open questions in the field, with the goal of stimulating further investigation that will advance basic knowledge and human health.

Resumo em Inglês:

Cryptococcosis diagnosis has been recently improved by the use of rapid cryptococcal antigen testing with lateral flow assays, which have proved sensitive and specific. Using “test and treat” screening strategies for cryptococcal disease with these tests has been showed effective in reducing cryptococcal meningitis (CM) in HIV-infected patients. Recommended induction, consolidation, and maintenance therapeutic strategy for CM is widely unavailable and/or expensive in low and middle-income settings. New therapeutic strategies, mostly using reduced duration, have recently shown acceptable outcome or are currently tested. Diagnostic and therapeutic guidelines for cryptococcal disease in limited resources countries are undergoing a paradigmatic shift.