Schistosomiasis research in the dongting lake region and its impact on local and national treatment and control in China

Schistosomiasis is a chronic and debilitating parasitic disease that has often been neglected because it is a disease of poverty, affecting poor rural communities in the developing world. This is not the case in the People's Republic of China (PRC), where the disease, caused by Schistosoma japonicum, has long captured the attention of the Chinese authorities who have, over the past 50-60 years, undertaken remarkably successful control programs that have substantially reduced the schistosomiasis disease burden. The Dongting Lake region in Hunan province is one of the major schistosome-endemic areas in the PRC due to its vast marshland habitats for the Oncomelania snail intermediate hosts of S. japonicum. Along with social, demographic, and other environmental factors, the recent completion and closure of the Three Gorges dam will most likely increase the range of these snail habitats, with the potential for re-emergence of schistosomiasis and increased transmission in Hunan and other schistosome-endemic provinces being a particular concern. In this paper, we review the history and the current status of schistosomiasis control in the Dongting Lake region. We explore the epidemiological factors contributing to S. japonicum transmission there, and summarise some of the key research findings from studies undertaken on schistosomiasis in Hunan province over the past 10 years. The impact of this research on current and future approaches for sustainable integrated control of schistosomiasis in this and other endemic areas in the PRC is emphasised.     

An overview of animal models in experimental schistosomiasis and refinements in the use of non-human primates.

The complex nature of the schistosome parasite and its interaction with the mammalian host necessitates the continued use of live intact animal models in schistosomiasis research. This review acknowledges this necessity and highlights some of the important insights into the pathogenesis of the disease that have been gained from using various animal models. The use of non-human primates as more relevant models of human schistosomiasis is stated. In addition, the importance of animal welfare consideration when using primates for research is emphasized. Finally, some guidelines for the refined capture, handling and early humane endpoints for non-human primates to be used in experimental schistosomiasis are suggested.     

The baboon as a non-human primate model of human schistosome infection

Over the past three decades, intensive studies of murine schistosomiasis have provided important clues to the understanding of the human disease, but growing evidence suggests that these results derived from highly inbred strains of mice might not have direct applicability to the human infection. Recent data based on the baboon indicate that infection in this non-human primate might mirror the human situation. In this review, Mramba Nyindo and Idle Farah demonstrate that baboons provide an excellent non-human primate model that produces pathology and disease closely resembling that observed in humans, and address how studies in baboons can provide insights into mechanisms regulating schistosomiasis mansoni pathology and immunity. They also address, in a general way, issues related to the use of non-human primates in biomedical research.     

Mechanisms of resistance to S. mansoni infection: the rat model

Human schistosomiasis is associated with IgE and eosinophilia, feature of a type 2 response. In experimental investigations, murine model has been widely used in order to dissect the immune responses involved in the expression of protective immunity or disease in Schistosoma mansoni infection. Collectively, observations made in this model and in humans demonstrated a strong contrast since a Th2 response in infected mice is involved in the expression of pathology, however, in infected humans the same type of response is rather beneficial for the host. This review will consider the relevance of extrapolating studies of immune responses from experimentally infected rats a semi-permissive host, to studies on S. mansoni infected humans.     

Schistosomiasis in infants and pre-school-aged children in sub-Saharan Africa: implication for control

Until recently, the epidemiology and control of schistosomiasis in sub-Saharan Africa have focused primarily on infections in school-aged children and to a lesser extent on adults. Now there is growing evidence and reports of infection in infants and pre-school-aged children (≤ 6 years old) in Ghana, Kenya, Mali, Niger, Nigeria and Uganda, with reported prevalence from 14% to 86%. In this review, we provide available information on the epidemiology, transmission and control of schistosomiasis in this age group, generally not considered or included in national schistosomiasis control programmes that are being implemented in several sub-Saharan African countries. Contrary to previous assumptions, we show that schistosomiasis infection starts from early childhood in many endemic communities and factors associated with exposure of infants and pre-school-aged children to infection are yet to be determined. The development of morbidity early in childhood may contribute to long-term clinical impact and severity of schistosomiasis before they receive treatment. Consistently, these issues are overlooked in most schistosomiasis control programmes. It is, therefore, necessary to review current policy of schistosomiasis control programmes in sub-Saharan Africa to consider the treatment of infant and pre-school-aged children and the health education to mothers.     

The control of schistosomiasis and soil-transmitted helminths in East Africa

As a result of support from the Bill and Melinda Gates Foundation, schistosomiasis and intestinal or soil-transmitted helminth infections have been the subject of national control programmes in three Eastern and Southern African countries: Uganda, the United Republic of Tanzania and Zambia. Here, we review the significant progress made in their control efforts and highlight the different approaches being adopted to ensure programme effectiveness and sustainability. Although a positive start has been made to reduce morbidity resulting from schistosomiasis and soil-transmitted helminth infections in these countries, it is imperative that support is identified to sustain the programmes until these infections are no longer a public health problem and children can therefore be given a healthy start to life.     

A systematic literature review of schistosomiasis in urban and peri-urban settings

BackgroundSchistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and belongs to the neglected tropical diseases. The disease has been reported in 78 countries, with around 290.8 million people in need of treatment in 2018. Schistosomiasis is predominantly considered a rural disease with a subsequent focus of research and control activities in rural settings. Over the past decades, occurrence and even expansion of schistosomiasis foci in peri-urban and urban settings have increasingly been observed. Rural–urban migration in low- and middle-income countries and subsequent rapid and unplanned urbanization are thought to explain these observations. Fifty-five percent (55%) of the world population is already estimated to live in urban areas, with a projected increase to 68% by 2050. In light of rapid urbanization and the efforts to control morbidity and ultimately achieve elimination of schistosomiasis, it is important to deepen our understanding of the occurrence, prevalence, and transmission of schistosomiasis in urban and peri-urban settings. A systematic literature review looking at urban and peri-urban schistosomiasis was therefore carried out as a first step to address the research and mapping gap.MethodologyFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic computer-aided literature review was carried out using PubMed, ScienceDirect, and the World Health Organization Database in November 2019, which was updated in March 2020. Only papers for which at least the abstract was available in English were used. Relevant publications were screened, duplicates were removed, guidelines for eligibility were applied, and eligible studies were reviewed. Studies looking at human Schistosoma infections, prevalence, and intensity of infection in urban and peri-urban settings were included as well as those focusing on the intermediate host snails.Principal findingsA total of 248 publications met the inclusion criteria. The selected studies confirm that schistosomiasis is prevalent in peri-urban and urban areas in the countries assessed. Earlier studies report higher prevalence levels in urban settings compared to data extracted from more recent publications, yet the challenge of migration, rapid uncontrolled urbanization, and resulting poor living conditions highlight the potential for continuous or even newly established transmission to take place.ConclusionsThe review indicates that schistosomiasis has long existed in urban and peri-urban areas and remains a public health problem. There is, however, a challenge of comparability of settings due to the lack of a clear definition of what constitutes urban and peri-urban. There is a pressing need for improved monitoring of schistosomiasis in urban communities and consideration of treatment strategies.     

Towards control of schistosomiasis in sub-Saharan Africa

Approximately 80% of the 200 million people infected with schistosomiasis inhabit sub-Saharan Africa, and the annual mortality is estimated to be 280,000. Praziquantel is the drug of choice in the treatment of schistosomiasis and pregnant women may now be treated. It was agreed at the World Health Assembly in 2001 that at least 75% of school-aged children in high burden areas should be treated for schistosomiasis and soil-transmitted helminth infections by 2010 to reduce morbidity. A grant from the Bill and Melinda Gates Foundation to the Schistosomiasis Control Initiative, Imperial College of Science, Technology and Medicine, London has enabled control programmes to be initiated in Uganda, Tanzania, Zambia, Burkina Faso, Niger and Mali. Additional programmes have recently commenced in Zanzibar with a grant from the Health Foundation to The Natural History Museum, London and in Cameroon. Combination treatment for schistosomiasis, gastrointestinal helminths and filariasis reduces costs of control programmes. The EC Concerted Action Group on 'Praziquantel: its central role in the chemotherapy of schistosome infection' met in Yaoundé Cameroon in 2004 to discuss recent developments in laboratory and field studies. The use of standard operating procedures will enable data on drug action on schistosomes produced in different laboratories to be compared. With the ever increasing use of praziquantel there is a possibility of the development of resistance by schistosomes to the drug, hence the necessity to explore the activities of other compounds. Artemether, unlike praziquantel, is effective against immature schistosomes. The effectiveness of mirazid, an extract of myrrh, is controversial as data from different laboratories are equivocal. It is suggested that an independent body such as the World Health Organization should determine whether mirazid should be used in the treatment of schistosomiasis.     

Are Ca2+ channels targets of praziquantel action?

Praziquantel is the current drug of choice for the control of schistosomiasis. It is highly effective against all species of schistosomes and shows minimal adverse effects. Though introduced for the treatment of schistosomiasis more than 20 years ago, the mode of action of praziquantel remains to be elucidated. This review will focus on advances in defining the molecular target of praziquantel action, with particular emphasis on recent work indicating an important role for voltage-gated calcium channels.     

Contribution of experimental models to the understanding of immunity to schistosomiasis]

The discovery of a functional division in T helper cells on the basis of their cytokine secretion patterns has changed our vision of immunological responses. This dichotomy has equally shown the complexity of immune responses since there is a well orchestrated cross-regulation of cytokine production induced by viral, bacterial or parasitic pathogens. In the context of type 1-type 2 cytokine pattern, mice has been universally and extensively used to associate an infectious disease according to each category in order to better understand human infections. However, with respect to schistosomiasis, immunological observations in mice have not been confirmed in humans and particularly the nature of the protective immune response. This report will consider the relevance of extrapolating from immunological studies on schistosome in experimentally infected rats to studies on naturally infected humans.     

Molecular studies of Biomphalaria glabrata, an intermediate host of Schistosoma mansoni

The freshwater gastropod Biomphalaria glabrata is one of the most important invertebrate hosts of the helminth parasite Schistosoma mansoni. Investigators are using different strategies to determine the molecular basis of this snail-parasite relationship. Of particular interest are the identification of parasite resistance genes in the snail, and the application of molecular probes to better understand the epidemiology of schistosomiasis. This review will focus on recent advances that have been made on genome analysis of B. glabrata. Much of this work has centred on the use of random amplification of polymorphic DNA-PCR-based technology, with restriction fragment length polymorphism analysis and the generation of expressed sequence tags from the snail. A brief discussion of how parasite products may complicate this analysis is also given, along with an indication of the scope of the problems that lie ahead.     

A vaccine against Asian schistosomiasis

There is continued transmission of schistosomiasis japonica in China and Philippines despite highly effective control programs that focus on the application of the highly effective drug praziquantel (PZQ). The massive Three Gorges Dam across the Yangtze River in Southern China, soon to be completed, is expected to significantly increase schistosomiasis transmission and introduce the disease into areas currently unaffected. After long-term experience it is generally accepted that PZQ chemotherapy, although the cornerstone of current control programs, does have significant limitations. Furthermore, efficient drug delivery requires a substantial infrastructure to regularly cover all parts of an endemic area. Although there is not yet clear-cut evidence for the existence of PZQ-resistant schistosome strains, decreased susceptibility to the drug has been observed in several countries. As a result, a protective vaccine represents an essential component for the long-term control of schistosomiasis. This article briefly reviews aspects of anti-schistosome protective immunity that are important in the context of vaccine development. The current status in the development of vaccines against Schistosoma japonicum will then be discussed as will new approaches that may improve on the efficacy of available vaccines, and aid in the identification of new targets for immune attack. With new and extensive data becoming available from the S. japonicum genome project, the prospects for developing an effective vaccine are encouraging. The challenges that remain are many but it is crucial that the momentum towards developing effective anti-schistosome vaccines is maintained.     

The role of interleukin-13 in infectious diseases and allergy

Cytokines, also referred to as interleukins, are the major orchestrators of host defence processes, and, as such, are involved in insults, repair and restoration of tissue homeostasis. This review summarises recent findings on and emerging models of the biological roles of the double-edged sword interleukin-13 (IL-13), which have been principally obtained from studies in mice that are deficient for IL-13, or its components. IL-13-mediated functions not only contribute to the susceptible phenotype in Leishmania major infection but also seem to play a protective role in chronic leishmaniasis. Moreover, IL-13 plays a key protective role in the expulsion of helminths from the gut while also actively contributing to the pathology in schistosomiasis. In allergic asthma, IL-13 has also been found to be a key factor. Therapeutic administration of an IL-13 inhibitor in mice successfully prevents both the allergic disease phenotype and schistosoma egg-induced lung pathology. If this scenario holds true in humans, we soon may have an efficient drug for treatment of IL-13-mediated diseases.     

Achievements of schistosomiasis control in China

The control of schistosomiasis has been spectacularly successful in terms of controlling endemicity and severity of the disease during the last 50 years. It can be categorized into two stages. From 1955 through 1980, the transmission-control strategy had been widely and successfully carried out. By the end of 1980, the epidemic of schistosomiasis was successfully circumscribed in certain core regions including areas at the middle and low reaches of the Yangtze River and some mountainous areas in Sichuan and Yunnan provinces, where control of schistosomiasis had been demonstrated to be very difficult to be sustained. Therefore, since 1980, schistosomiasis control in China has been modified to employ a stepwise strategy, based on which morbidity control has been given priorities and if possible transmission control has been pursued. However, since snail-ridden areas remain unchanged so far, reinfections occur frequently. This necessitates a maintenance phase to consolidate the achievements in the control of schistosomiasis. In the mean time, we are challenged with some environmental, social and economical changes in terms of controlling schistosomiasis. Successfully controlling schistosomiasis in China is still a long-term task but will be achieved without doubt along with the economic development and the promotion of living and cultural standard of people.     

Biotechnological advances in the diagnosis,species differentiation and phylogenetic analysis of Schistosoma spp.

Schistosomiasis is a serious parasitic disease caused by blood-dwelling flukes of the genus Schistosoma. Throughout the world, schistosomiasis is associated with high rates of morbidity and mortality, with close to 800 million people at risk of infection. Precise methods for identification of Schistosoma species and diagnosis of schistosomiasis are crucial for an enhanced understanding of parasite epidemiology that informs effective antiparasitic treatment and preventive measures. Traditional approaches for the diagnosis of schistosomiasis include etiological, immunological and imaging techniques. Diagnosis of schistosomiasis has been revolutionized by the advent of new molecular technologies to amplify parasite nucleic acids. Among these, polymerase chain reaction-based methods have been useful in the analysis of genetic variation among Schistosoma spp. Mass spectrometry is now extending the range of biological molecules that can be detected. In this review, we summarize traditional, non-DNA-based diagnostic methods and then describe and discuss the current and developing molecular techniques for the diagnosis, species differentiation and phylogenetic analysis of Schistosoma spp. These exciting techniques provide foundations for further development of more effective and precise approaches to differentiate schistosomes and diagnose schistosomiasis in the clinic, and also have important implication for exploring novel measures to control schistosomiasis in the near future.     

Schistosoma mansoni egg glycoproteins and C-type lectins of host immune cells: molecular partners that shape immune responses

Schistosome eggs and egg-derived molecules are potent immunomodulatory agents. There is increasing evidence that the interplay between egg glycoproteins and host C-type lectins plays an important role in shaping immune responses during schistosomiasis. As most experiments in this field so far have been performed using complex protein/glycoprotein mixtures or synthetic model glycoconjugates, it is still largely unclear which individual moieties of schistosome eggs are immunologically active. In this review we will discuss molecular aspects of Schistosoma mansoni egg glycoproteins, their interactions with C-type lectins, and the relevance to schistosome egg immunobiology.     

Fibrillin: from domain structure to supramolecular assembly.

In the last 5 years, significant progress has been made in understanding the structure and function of all the major domains composing the fibrillins. A previous review [Meth. Enzymol. 245 (1994), 29] focused on the isolation of fibrillin monomers and fibrillin-containing polymers (microfibrils). In this article, information gained from recent studies which have further elucidated molecular structure and investigated effects of mutations on structural and functional properties will be summarized. In addition, studies of functional domains in fibrillins which may be important in assembling microfibrils will be discussed. Throughout this review, the authors have attempted to identify areas of research which have been controversial. In the conclusion, we raise important questions which remain unresolved.     

Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective?

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. Recent studies of signaling proteins in schistosomes uncovered a way of achieving this goal relatively quickly. It was shown that protein kinases (PKs) control important biological processes in schistosomes. Concurrently, the involvement of mutant forms of PKs was demonstrated in the etiology of cancer. Therefore, different anticancer drugs have been developed to inhibit deregulated PKs. These can also inhibit schistosome PKs, thus blocking parasite development. Recent studies characterizing schistosome PKs are summarized and we discuss the concept of PK inhibitors, including approved cancer drugs, as novel candidate anti-schistosome agents. This is also likely to be of significance for other worm infections.     

Schistosomiasis Transmission Model and its Control in Anhui Province

National Bureau of Statistics of China reports that the incidence of schistosomiasis has been increasing in recent years. To study dynamic behaviors of schistosomiasis transmission, based on practical experience of staff in Anhui Institute of Schistosomiasis, a mathematical schistosomiasis model with reinfection of recovered people is established in this paper. Metzler matrix theory and center manifold theorem are used to analyze stability of equilibria. Parameter estimation has been performed by combining model and monitoring data. It is found that the basic reproduction number is different every year. The most concern of Institute of Schistosomiasis is whether or when to kill snails every year. To answer this question, threshold value of snail density can be obtained. Once the snail density exceeds the threshold, the staff will need to kill snails. To find the best control measures, sensitivity analysis is used to find out sensitive parameters, and then control measures can be obtained by optimization control measures. The results show that combination of spraying molluscicide, publicity and education, improving the health facilities, and large-scale treatment of patient groups have the best effect. In additional, it is found that the number of patients does not change much when the reinfection rate of recovered people is very small. However, when the reinfection rate is slightly larger, the number of patients will suddenly increase to a large value.