Biological control of Biomphalaria, the intermediate host of Schistosoma spp.: a systematic review

ABSTRACT: Schistosomiasis is an important vector-borne disease transmitted by an intermediate host: a freshwater mollusk. Control of these snail vectors is one of the strategies of the World Health Organization against the disease. The present study was based on a systematic review of published scientific papers concerning the biological control of snails (genus Biomphalaria), and identified the ongoing challenges and propose future perspectives. The review methodology was based on the PRISMA statement, the international databases Web of Science and Scopus for the period 1945-2021. In total, 47 papers were analyzed, published by authors from 14 different countries, the majority being from: France, Brazil, the United States, and Egypt. The most widely used strategy for biological control was predation by fish (12 studies). Fourteen papers were published in the most prolific decade 2010-2019; during which there was also a greater diversity of biological control agents in studies. In this context, we believed that one of the principal challenges of this approach is the successful simultaneous use of multiple types of biological control agent: predators, competitors, and/or microbial agents. This new approach may provide important insights for the development of new biological control agents or microbial-based products, with the potential to reduce the parasite load carried by schistosomiasis snail vector and control its transmission in a sustainable way.


INTRODUCTION
Schistosomiasis, caused by Schistosoma spp., has the second greatest socioeconomic impact of any parasitic disease (after malaria) and is one of the neglected tropical diseases.Globally, it is the principal freshwater gastropod borne disease, and is present in 78 countries, with an estimated 240 million infected individuals.A further 700 million are at risk worldwide in endemic areas (WHO, 2020).Overall, Ciência Rural, v.53, n.4, 2023.Friani et al. 51 of the 78 countries apply preventive chemotherapy annually, and 18 have reported the cessation of transmission; although, this has yet to be confirmed (WHO, 2021).The World Health Roadmap of the World Health Organization (WHO) aimed the eradication of schistosomiasis as a priority public health target.
Species of Schistosoma are transmitted through the establishment of interactions between the definitive (human and non-human) and intermediate (snails) hosts in a limnic environment.Transmission to the vertebrate host occurs when the larvae of the parasite (cercariae), are released by infected freshwater snails and penetrate human skin, or in the case of aquatic rodents enter via the interdigital membranes (COLLEy et al., 2014).The snail intermediate host is infected via contamination of the limnic ecosystem, by human and animal feces that contain the parasite eggs.Recently, viable hybridization and introgression have been found under natural conditions in Europe and Africa, both between and within human and animal schistosomes (LÉGER et al., 2016;LÉGER & WEBSTER, 2017;KINCAID-SMITH et al., 2017;LÉGER et al., 2020).This raises important questions in relation to measures for the control of transmission and the elimination of this disease, given its impact on public health, and its potential for rapid adaptation in areas in which it is endemic.
The main types of schistosomiasis control interventions are preventive chemotherapy, individual diagnostic tests, treatment with praziquantel, control of snail populations and health education (WHO, 2021).However, the financial costs of diagnosis and treatment should be considered alongside wider social and environmental costs and benefits when planning a truly integrated disease control strategy (SALARI et al., 2020).However, in addition to the costs of diagnosis and treatment, other social and environmental measures of incalculable value should also be considered when planning a true One Healthbased strategy for disease control (CDC, 2020).
Environmental measures for the control of schistosomiasis include reducing environmental contamination and preventing infection of human and non-human hosts.To achieve this, STAUFFER & MADSEN (2018) recommend controlling the snail vector population through chemical or biological means, eliminating cercariae released by snail intermediate hosts without killing the snails, and reducing infection rates in areas of transmission.The current recommendation for snail vector control is a chemical product, niclosamide, but well-structured biological control is also being encouraged, given that chemical control causes problems such as the death of non-target organisms and contamination, preventing the use of the water resource for a period of time, and high cost (WHO, 2017).

History of schistosomiasis control initiatives, focusing on biological control
The control of vector snail populations is one of the strategies recommended by the WHO for the control of schistosomiasis (BARBOSA et al., 2008).In its early reports (WHO, 1961(WHO, , 1965(WHO, , 1967)), the WHO emphasized the need for the control of snail populations as the most effective measure against endemic schistosomiasis, given the lack of efficacy of the therapeutic drugs available at the time.The application of molluscicides is recommended in combination with the establishment of adequate public sanitation and drinking water supplies.
In the 1970s (WHO, 1973), schistosomiasis control faced challenges worldwide because of a major lack of both resources and qualified personnel (BARBOSA et al., 2008).The most important goal of this period was to reduce the spread of the disease into intermediate areas based on the treatment of infected individuals and the concomitant application of chemical molluscicides, such as niclosamide, in endemic areas.One of the most important aspects of this report was that it discouraged the biological control of snails, particularly where studies of environmental impact were unavailable (WHO, 1973).
Two reports were published in the 1980s (WHO, 1980(WHO, , 1985)).In the first, the emphasis was still on the control of transmission, whereas in the second, the focus shifted to the control of morbidity through the diagnosis and treatment of infected individuals.The 1980 report emphasized biological control by means of predatory snails, such as Marisa cornuarietis, which were used to reduce the transmission of schistosomiasis on a large scale in Puerto Rico.However, the committee recommended that snails from endemic areas should not be transferred or maintained in laboratories in other endemic areas for any purpose, discouraging studies on biological control (WHO, 1980).
In the 1990s and 2000s, chemotherapy became the principal control measure for schistosomiasis, in an integrated disease control program that also targeted geohelminthiasis to reduce costs (WHO, 1993).In the 1990s, school-children with a prior diagnosis were the principal targets of treatment, and in the 2000s, treatment focused on highrisk groups (children and adults involved in activities with a high risk of infection) without prior diagnosis.
Over the last 20 years, WHO experts have published three recommendations (2001,2012,2017,2022).The first report broadened the focus on the control of schistosomiasis morbidity (reduction of 75-100% in schoolchildren and women) and made no mention of the control of snail populations.The 2012 resolution focused on public policies to eliminate endemic schistosomiasis in affected countries.It recommended strengthened epidemiological monitoring, preventive chemotherapy, and sanitary interventions, such as public sanitation systems, supplies of clean drinking water, and elimination of vector mollusks, but did not address the avoidance of potential environmental impacts.In 2017 (WHO, 2017), the report recommended integrated vector control, broad studies of vectors and their local transmission patterns, and the development of different biological and other control strategies to assess their impact on the disease when combined with other types of intervention, such as drugs and vaccines.In 2022, the recommendation is directed toward public health campaigns to ensure high acceptance of snail control interventions.With development of snail control programs for the larger and less expensive global supply of molluscicides.In addition, the development and evaluation of new and environmentally friendly molluscicides are encouraged (WHO, 2022).
Schistosomiasis control measures are currently aligned with the One Health approach, which involves integrated vector control measures.There is a clear need for sustainable ecological control measures that preserve the environment, other animals, and local human populations, as mandated by the systemic schistosomiasis control model of the One Health concept (CDC, 2020).In this context, the present study provided a systematic review of the scientific papers published on the biological control of Biomphalaria, the intermediate host of schistosomiasis, and evaluates current challenges and future perspectives.

Methods
The present study was based on a systematic literature review, following the PRISMA guidelines (MOHER et al., 2009;PAGE et al., 2021), of the Web of Science and Scopus international databases, covering the 76-year period between 1945 and 2021.The review consisted of three steps: (i) identification of papers in the Web of Science and Scopus databases that contained specific descriptors, in addition to papers from other sources that were not detected by the descriptors but were relevant to this review; (ii) screening (omitting duplicate, reviews, and mathematical models, as well as unavailable papers and those beyond the scope of the present study), of papers in English, Portuguese, and French published in indexed journals and available for download; and (iii) the inclusion of eligible full-text papers that were available online (Figure 1).The search phase looked for the descriptors "schistosomiasis and biological control" or "Biomphalaria and biological control", in the titles or keywords of the papers.
All the studies identified through this search were read in full, classified as field or laboratory research, by biological agent analyzed (bacterium, fungus, invertebrate or vertebrate), and by the type of control (predation, competition or microbial control).The studies were analyzed quantitatively in terms of the number of papers per type of biological agent, the decade of publication, and country of origin.

Analysis of the papers included in the present study
In total, 98 papers were identified during the search of the Scopus (46) and Web of Science (52) databases in June 2021.A further 23 papers that were not identified using the descriptors were also added to the list of references.Twenty-one of these papers were excluded due to duplication or failure to satisfy the study's inclusion criteria.Of these, only 47 were available for download and were analyzed for the present review (Figure 1).
The biological strategy most commonly used to control Biomphalaria populations throughout the study period was predation using fish (12 papers), with the first paper on this subject being published in 1946.Other types of biological control involved two snail species, Marisa cornuarietis (Ampullariidae) (six papers), and Melanoides tuberculata (Thiaridae) (five papers).The Biomphalaria species most often targeted in the studies was B. glabrata (23 papers), followed by B. pfeifferi (12 papers).In the case of microbiological and parasitic agents, 5 papers focused on bacteria, four on fungi, and two on helminths.
The most prolific decades in the present study were 2010-2019 (14 papers), 1990-1999 (10 papers), and 1980-1989 (eight papers).In the Ciência Rural, v.53, n.4, 2023.1980s and 1990s, predation was the biological control strategy evaluated in most studies, i.e., four and five papers, respectively.During this period, six studies focused on snails as both predators and competitors.We highlighted the research on M. cornuarietis in Puerto Rico and the studies of thiarids in the West Indian islands of Saint Lucia, Martinique, and Guadeloupe (PRENTICE, 1983;POINTIER, 1989;1993;GIOVANELLI et al., 2003).It is important to note here that the success of the biological control program in Puerto Rico using M. cornuarietis, which began in the 1950s and generated key results in the 1970s and 1980s, led the WHO to recommend the use of this snail as a biological control agent in its reports published in the 1980s.Even after the use of snails became less popular, (POINTIER et al., 1991;SOKOLOW et al., 2015), further research was conducted in the 1990s and early 2000s before being discontinued.
A greater diversity of biological agents, reported in 14 papers, was studied for the control of Biomphalaria between 2010 and 2019.The large number of papers published in this most recent period may reflect the WHO recommendations on integrated vector management, which encourage detailed local study of the problem in a given region with the aim of identifying local solutions.Predation was an ongoing theme (seven papers), but new agents such as waterbugs, fly larvae, and prawns were also included.The remaining seven papers discussed microbiological and parasitological agents, including fungi (three papers), bacteria, and helminths (two papers each).

Agents of biological control
The concept of biological control has been redefined many times in recent years; we adopted the following definition, proposed by EILENBERG et al. (2001): "The use of living organisms to suppress the population density or impact of a specific pest organism, making it less abundant or less damaging than it would otherwise be."Biomphalaria, it should be noted, is an organism that acts as a transmitter of a neglected disease, rather than as a pest itself.Biological control in this case has the objective of reducing the transmission of schistosomiasis through the control of this intermediate host.
Over the years, control of Biomphalaria snail populations has been attempted, using direct (predation) or indirect (competition for food or habitat) mechanisms or ecological interactions (AROSTEGUI et al., 2019); the various agents can be classified as either microbial control (viruses, fungi, protozoa, and bacteria), predators, or competitors (POINTIER & JOURDANE, 2000) and are detailed below, organized into these three types.
Two species of snail, Marisa cornuarietis and Pomacea sp., have been tested as potential predators of Biomphalaria.In the laboratory, CHERNIN et al. (1956a) evaluated the conditions under which M. cornuarietis could limit the growth of Biomphalaria populations by preying on egg masses and newly hatched snails.In 1956, owing to the high cost of the chemicals used to control schistosomiasis, the Puerto Rican government decided to implement a biological control project that focused on irrigation ponds, using M. cornuarietis as the control agent.It was possible to confirm the effectiveness of M. cornuarietis as a predator/competitor of B. glabrata in the field, and obtain a 60-fold reduction in the cost of controlling B. glabrata (RUIZ-TIBÉN et al., 1969).Two decades later, POINTIER et al. (1991) introduced M. cornuarietis to the West Indian island of Guadeloupe; POINTIER & DAVID (2004) monitored the effect of the subsequent 13 years and reported convincing evidence that M. cornuarietis played an important role in the disappearance of B. glabrata in the region.
Leeches of the genus Helobdella have also been tested as potential predators of Biomphalaria.CHERNIN et al. (1956b) found that H. fusca could control the snail population.Other authors have reported that H. triserialis is a predator of new hatched, juvenile, as well as adult, B. glabrata, B. straminea and B. tenagophila (GUIMARÃES et al., 1983;1984).Crayfish (Procambarus clarkii) reduced the abundance of B. pfeifferi (HOFKIN et al., 1991;1992)

Competitors
The first studies focusing on the competitors of Biomphalaria were published in the 1950s; although, papers on this topic are still scarce.These competitors (Tables 4 and 5) consist of a number of other snail species.Several studies have verified the effects of the interspecific competition between M. cornuarietis and Biomphalaria in the field.FERGUSON et al. (1958) reported that Biomphalaria had disappeared completely from ponds two years after the introduction of M. cornuarietis.Similar results were obtained by OLIVER- GONZALEZ & FERGUSON (1959), who recorded the almost complete elimination of Biomphalaria from streams 18 month after the introduction of M. cornuarietis and, more importantly, the absence of new schistosomiasis infections in a study group of preschool children.RUIZ-TIBÉN et al. (1969)    Marisa and Biomphalaria, emphasizing the low cost of introducing the competitor and the simplicity of this strategy of biological control.However, no other studies of this species in different localities were identified by our search strategy, nor were there any current studies on the program implemented in Puerto Rico using M. cornuarietis.
A relationship between Melanoides (=Thiara) tuberculata and Biomphalaria has also been observed in the field.POINTIER (1989;1993) reported a rapid spread of M. tuberculata, that resulted in a marked reduction in the number of B. glabrata.PRENTICE (1983) and MKOJI et al. (1992) have suggested that Thiara granifera and B. glabrata compete for both space and food, and that B. glabrata in the field.
The relationship between Pomacea spp.and Biomphalaria has also been studied.Initially, Pomacea prevents the establishment of active colonies of B. glabrata, causing mortality among the newly hatched B. glabrata snails and reducing the number of B. glabrata feeding on its own egg masses  ( PAULINyI & PAULINI, 1972).The accidental introduction of Ampullaria glauca into a natural lake led to a marked decline in the local B. glabrata population, until only a small colony remained.The presence of A. glauca may also have caused a marked decline in the presence of Pistia stratiotes, a floating plant that provides a favorable habitat for B. glabrata.Another consequence was a decline of S. mansoni in the local rat population (POINTIER, 1988;POINTIER et al., 1991).COELHO et al. (2004) also proposed a biological control model using the Taim strain of B. tenagophila, which is resistant to S. mansoni infection.However, the proposed model is based on the introduction of a resistant strain following the application of a chemical molluscicide.The authors also generated transgenic B. glabrata harboring the S. mansoni resistance gene.The use of genetic techniques to manipulate schistosomiasis host snails has been indicated as a potential complementary tool to reduce or even interrupt transmission.

Microbial control
Entomopathogenic agents, such as fungi, bacteria and nematodes, have been successfully used to control a number of arthropod pests, including Mahanarva fimbriolata, Deois flavopicta, Cornitermes cumulans, and Rhipicephalus microplus (FERNANDES & ALVES, 1991;FERNANDES & BITTENCOURT, 2008;PEREIRA et al., 2008;LOUREIRO et al., 2012).Such agents have also been used recently for the microbial control of Biomphalaria snails (DUARTE et al., 2015;DUVAL et al., 2015;OKONJO et al., 2015;SAAD et al., 2016;ABD EL-GHANy & ABD EL-GHANy, 2017;ABDEL-WARETH et al., 2019).Entomopathogenic fungi, bacteria, and nematodes are environmentally friendly and are thus considered sustainable method for the  & JARONSKI, 2016;MASCARIN et al., 2019).DUARTE et al. (2015) reported the action of two well-known entomopathogenic fungi (Beauveria and Metarhizium) against B. glabrata egg masses: the fungi penetrated the eggs and reached the embryos, thus impairing egg maturation.OKONJO et al. (2015) recorded up to 70% mortality in adult B. pfeifferi exposed for 28 days to entomopathogenic nematodes.Several bacteria have also been shown to exhibit molluscicidal activities.DUVAL et al. (2015) described a novel Paenibacillus strain that affects both the adult and embryonic stages of B. glabrata, causing significant mortality.These microbial control studies reflect the considerable global momentum attained by biopesticide research, in recent years, which has been supported by both social and governmental demands for more sustainable invertebrate pest control methods (Table 6).Ciência Rural, v.53, n.4, 2023.

Challenges
There is no single species capable of controlling populations of Biomphalaria spp. in the various local endemics settings, wherefore concurrent use of a few species, depending on the ecosystem, should be considered.The development of multi-agent solutions is one of the challenges for the control of these vectors and should reduce the population and have an impact on the transmission of schistosomiasis.Each location will require a solution that accommodates the characteristics and unique diversity of that location, that is, there is no single solution.
However, the introduction of an exotic species into an ecosystem may threaten its environmental integrity (WHO, 1980), and the introduction of more than one species into the same ecotope could be disastrous.In the face of this, developing sustainable biological controls that can be used to impede disease transmission will be difficult.Further clear challenges are the need to compile a detailed database of the organisms reported in the principal areas of disease transmission and to enhance the application of natural local biological agents affecting vector snails in each region.SOKOLOW et al. (2015), who used a local population of prawns that naturally consume newly hatched snails, to develop a sustainable local control strategy, adopted this approach.From this perspective, biological control has the advantage of not only controlling the host of S. mansoni, but also improving the quality of life of the local human population affected by schistosomiasis, using natural predators, competitors, parasites, or established biocontrol agents (SOKOLOW et al., 2017).As mentioned above, biocontrol agents, particularly fungi and bacteria, have attracted increasing attention over the past 10 years (DUARTE et al., 2015;DUVAL et al., 2015;SAAD et al., 2016; ABD EL-GHANy & ABD EL-GHANy, 2017).These microorganisms, some of which are natural to the microbiome of either the target animal or its aquatic environment, may function as disruptors of either physiological mechanisms or microbial biodiversity.From this perspective, the microbiome  Given this, one further challenge for effective biological control is to use microorganisms as the active ingredient of a product that can be used for the indirect control of schistosomiasis transmission.This would be a natural product intended to provoke a homeostatic imbalance in snails, particularly, those infected with S. mansoni.This imbalance would reduce the parasite load of the vector or provoke its death, culminating in a selective control.However, it is necessary to identify, test, and in minute detail the impact of different microorganisms, at different concentrations, on the dynamics of the Biomphalaria/ Schistosoma interaction.

Future perspectives
Despite the effectiveness of schistosomiasis control programs based on the large-scale treatment of populations with drugs, the disease persists as a major public health problem in most endemic areas.Fundamental to success will be a holistic understanding the disease.Schistosomiasis is a systemic disease that involves intermediate hosts (snails) and definitive hosts, such as rodents, cattle, and humans that can migrate and spread the disease to new areas.The disease cycle also involves the limnic environments inhabited by host snails, which are also the final destination of domestic, medical, and industrial effluents in many countries with endemic diseases.While a holistic perspective, which relates the links in the epidemiological chain systematically, is essential to combat schistosomiasis effectively, it has yet to be put into practice.Based on the One Health concept, we suggested a differentiated approach and the implementation of strategies that protect not only public health, but also the integrity of the environment.Integrated, effective, and sustainable control should focus primarily on the control of transmission rather than morbidity, and be based on the application of local knowledge.
Based in the papers analyzed in this study, biological control is a promising measure for the control of schistosomiasis transmission, in contrast to the use of chemical molluscicides, which are expensive, environmentally unsafe, and toxic to many non-target organisms.However, to use this strategy we suggest ecological studies to identify possible competing organisms, predators, and/or microorganisms in the water or microbiota of mollusks in the region.These studies could be conducted in partnership with researchers from local research institutions and the affected community.It is important to maximize the avoidance of products, substances, and biological control agents that could in any way destabilize the local ecosystem or harm the local population.In this scenario, biological control constitutes an important complementary measure to be integrated with systemic controls, such as chemotherapy, large-scale environmental and sanitation programs, and the implementation of environmental and health education for populations at higher risk of the disease.

CONCLUSION
Based on the findings of our review, we encourage further research into the microbiota of the snail vectors.This would involve not only the identification of the microorganisms present in the normal microbiota, but also those associated with the susceptibility of the snails to Schistosoma infection We also encouraged research into local free-living microorganisms or those present in the microbiota of other aquatic organisms, which may interact with the snail vectors.These microbial agents may have potential as physiological disruptors and reproductive and/or epigenetic agents that could be used to alter the dynamics of the interaction between Biomphalaria and Schistosoma.This approach may reveal potential biological control agents or other microbial products that can reduce the parasite load of schistosomiasis vectors and control their transmission in a sustainable manner.

Figure 1 :
Figure 1: PRISMA 2020 flow diagram in this systematic review.
. The same was observed for B. alexandrina both in field experiments and in the laboratory (KHALIL & SLEEM, 2011).Freshwater prawns of the genus Macrobrachium have been studied in relation to their potential for regulating Biomphalaria populations in the field.SAVAYA et al. (2014) suggested restocking male prawns as a means of controlling local snail populations and reducing the prevalence of schistosomiasis in a region affected by dam construction.SOKOLOW et al. (2015) confirmed that reintroduction of the prawn after its extirpation resulted in a significant reduction in not only the population of infected snails but also the prevalence of schistosomiasis in the region; the prawns feed on the eggs, newly hatched snails, and other small individuals.Larvae of the fly Sepedon ruficeps have been tested as biological control agents for B. pfeifferi.The larvae have a high predation capacity, with one larva consuming up to 40 snails(AGBOHO et al., 2017).Waterbugs (Sphaerodema urinator) can find, attack, and devour snails, preferring small individuals of B. alexandrina(yOUNES et al., 2017).
reported the implementation of a M. cornuarietis biological control program for B. glabrata populations in natural ponds on the island of Puerto Rico, as an alternative to chemical controls.The 20-year follow-up showed Ciência Rural, v.53, n.4, 2023.

Friani
et al. that B. glabrata populations declined gradually, and were eventually replaced by M. cornuarietis.While this may have been beneficial in terms of disease control, the authors felt that the introduction of M. cornuarietis may eventually have led to ecological disruptions due to the elimination of B. glabrata populations.JOBINS & BERRIOS-DURAN (1970) discussed the competitive relationship between

Table 1 -
Summary of the content of the peer-reviewed papers on biological control of Biomphalaria species using predators from 1946 to 1984.
M. cornuarietis (snail) B. glabrata Adults No The disappearance of B. glabrata coincided with the introduction of Marisa RUIZ-TIBEN et al. (1969) Pomacea sp.(snail) B. glabrata Egg mass/ newly hatched No Pomacea sp.caused a reduction in the number eggs and impeded the establishment of B. glabrata colonies A. alluaudi reduced the number of B. pfeifferi.T. zilliie and T. leucosticta did not appear to be associated with reduction in the snail populations MCMAHON et al.

Table 2 -
Summary of the content of the peer-reviewed papers on biological control of Biomphalaria species using predators from 1990 to 2011.

Table 3 -
Summary of the content of the peer-reviewed papers on biological control of Biomphalaria species using predators from 2014 to 2018.

Table 4 -
Summary of the content of the peer-reviewed papers on biological control of Biomphalaria species using competitors from 1958 to 1989.

Table 5 -
Summary of the content of the peer-reviewed papers on biological control of Biomphalaria species using competitors from 1991 to 2004.

Table 6 -
Summary of the content of the peer-reviewed papers on biological control of species using microbial control.