Immunopathogenic Mechanisms in Human Schistosomaisis

Yuesheng Li, M.D., Ph.D.

Hunan Institute for Parasitic Diseases

Funded in September, 2006: $440000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS .

LAY SUMMARY

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Understanding Immune Responses in Schistosomiasis May Lead to Vaccine Development

This consortium will study immune responses in the tissues of human patients suffering from schistosomiasis, a parasitic infection prevalent in China and many other parts of the world. Improved understanding of the chronic disease process inherent in schistosomiasis, and the roles played by immune cells may provide clues that will eventually lead to the development of a vaccine to prevent this widespread disease.

About 200 million people worldwide are afflicted with schistosomiasis. It is caused by parasitic worms that enter humans (in larval form) when they bathe or swim in contaminated fresh water. The larvae then develop into adult male and female worms, which mate and produce eggs that are released into the blood stream. Acute infections respond to the drug Praziquantel, but drug costs often make it inaccessible to people in many parts of the world. Additionally, in some people, the immune response to the eggs actually triggers severe disease, affecting the liver and spleen, which can be chronic and fatal. Accordingly, severe schistosomiasis has been termed an “immunological diseases caused by an inappropriate 'host' response.” While studies in mice provide important information on the disease process, inferences concerning immune responses pertaining to humans are problematic.

With a new clinical management initiative in China, however, Consortium researchers have a new opportunity to extend immune studies in schistosomiasis to human tissues. There, patients with sever schistosomiasis undergo surgical removal of the spleen and biopsy of the liver to ameliorate the effects of advanced disease. The researchers will study tissues from a total of 200 people, including 150 patients and 50 controls who undergo such surgery due to accidents damaging these organs. Through these studies, the investigators will try to identify the processes leading to liver and spleen damage in those who develop advanced disease, and the key genes that appear to play a role in this disease progression. The results may pave the way to develop a vaccine to protect against schistosomiasis.

Specifically, they hypothesize that the way two immune T cell attackers, called “Th1” and “Th2” cells (which have different effects), act and are regulated determine whether the disease progresses to an advanced stage in humans. Additionally, they hypothesize, development of several physiological hallmarks of the disease—that occur in the vein drawing blood from the digestive tract to the liver, and in the liver and spleen—are influenced by a specific immune ”cytokine” called IL-13 (A cytokine is an immune protein that affects the behavior of other cells.) Moreover, people with strong IL-13, coupled with weaker IL-10 and IFN-γ cytokines may be especially at risk for severe disease. Therefore, the researchers will also determine whether variations in genes producing cytokines may contribute to greater risk.

Researchers from the Hunan Institute of Parasitic Diseases will collect and prepare the tissue samples from patients and controls in China; investigators from the Queensland Institute of Medical Research in Australia and the National Institutes of Health in America will undertake the study of the immune responses and the genetic analysis of the tissues.

Significance: If the research is able to characterize the processes involved in the development of severe schistosomiasis and the immune responses that are responsible for the disease's progression, the findings may lead to the development of an effective vaccine against this parasitic disease.

ABSTRACT

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Immunopathogenic Mechanisms in Human Schistosomaisis

Background: Schistosomiasis is a chronic parasitic disease responsible for 200 million human infections and an estimated 300,000 deaths each year. The causal agents are trematode helminth worms of the genus Schistosoma. In schistosomiasis, most chronic morbidity is related to the T-cell-dependent immune response of the host, directed against schistosome eggs. Disease develops primarily as a consequence of trapped eggs in liver, leading to marked CD4+ T cell programmed granulomatous inflammation, akin to a form of delayed-type hypersensitivity, tissue eosinophilia, collagen deposition and severe hepatic periportal (Symmers) fibrosis.

Experimental schistosome infections have been used to model features of human immunopathology and disease, particularly the mechanisms associated with granuloma formation and subsequent fibrotic scarring. IL-13 is the primary fibrogenic mediator in murine schistosomiasis, whereas TNF, IFN-gamma and IL-12 seem to have marked antifibrotic activity. These mechanisms are not easily investigated in humans with available knowledge on human responses to schistosomes falling far short of what is known in mice. Caution is required in extrapolating and interpreting results from murine experiments because, in many respects, the infection is dissimilar to the clinical situation. Thus, these studies need to be fully validated in humans.

This project will investigate the immunopathogenic mechanisms, particularly the contribution of type-1 and type-2-cytokines, influencing granuloma formation and the development of severe hepatosplenic disease due to Schistosoma japonicum in a large Chinese study cohort.

Outcomes and Significance: The availability of material from this unique patient series provides an unprecedented opportunity for studying Th1- and Th2-cytokine profiles influencing the dynamics of schistosome-induced fibrogenesis, the development of the granulomatous inflammation, and the progression to the severe forms of chronic schistosomiasis directly in diseased human liver and spleen target tissues. Direct correlations of expression levels of pro- and anti-fibrotic cytokines will be made with histological measures of disease severity. Further, the study will shed light on whether IL-13-dependent signaling pathways influence development of fibrosis, portal hypertension and hepatosplenic disease, and reveal contributions of previously unappreciated disease mechanisms to schistosome-induced liver pathology.

Since fibrosis and chronic inflammation is important to many other diseases such as Crohn’s disease, sarcoidosis, asthma, graft rejection, and several autoimmine diseases, this work will translate such as to have wide significance for human health.

INVESTIGATOR BIOGRAPHIES

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Yuesheng Li, M.D., Ph.D.

Yuesheng Li, M.D., Ph.D., is Professor and Director of the Hunan Research Institute of Parasitic Diseases-CDC, Yueyang, Hunan Province, the People's Republic of China. He is also a NHMRC Research Fellow in Public Health and Visiting Scientist at The Queensland Institute of Medical Research. Dr Li earned his M.D. from Hunan Medical University, China, in 1975, obtained his Ph.D. from the University of Queensland in 2000, and, in 2005, he received a Howard Hughes Medical Institute International Research Scholarship, the first Chinese scientist to receive this award. He is a physician/scientist and specialist in population health and infectious diseases, who has worked on the immunogenetics, epidemiology, and the control and clinical management of schistosomiasis in China for more than 25 years. He has accumulated vast experience in undertaking longitudinal surveys for identifying patients with chronic and advanced schistosomiasis. He has a particular research interest in understanding the processes involved in the pathology of schistosomiasis and he is a prolific writer, having published more than 100 research papers and review articles. Dr Li's home Institute is situated in Yueyang City, close to the Dongting Lake, a major endemic area for schistosomiasis in China, and it is recognized as one of the main provincial institutes specializing in parasitic diseases in China.

Thomas A. Wynn, Ph.D. is Senior Investigator and Head, Immunopathogenesis Section, Laboratory of Parasitic Diseases (LPD) , National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), in Bethesda, Maryland. He holds a B.A. in Microbiology and a B.S. in Chemistry from Miami University in Ohio (1986), and received his Ph.D. from the Department of Medical Microbiology and Immunology University of Wisconsin Madison Medical School in 1991. Prior to his current position, he was an IRTA Postdoctoral Fellow (1991-1995), Staff Fellow (1995-1997) and Investigator (1997-2001) in the Immunobiology/Immunology and Cell Biology Sections, LPD, NIAID, NIH.

Dr Wynn's research focuses on understanding the molecular and immunological mechanisms regulating the pathogenesis of schistosomiasis and other granulomatous diseases and on developing a more defined and rational approach to new intervention strategies, including vaccine development. He is recognized as one of the most innovative scientists currently working on the pathology of murine and human schistosomiasis. A major emphasis of his research program has been to dissect the contributions of type-1 and type-2-associated cytokines to the pathogenesis of schistosomiasis. Dr Wynn's recent research has exploited microarray analysis to further characterize novel aspects of the Th1/Th2 paradigm in schistosome-induced pathogenesis, and his team is at the forefront of this technology that is exploring the molecular mechanisms involved in fibrogenesis, collagen deposition, granuloma formation, and the progression to hepatosplenic disease.

Donald P. McManus, Ph.D., D.Sc., is Senior Principal Research Fellow and Head of the Molecular Parasitology Laboratory at the Queensland Institute of Medical Research (QIMR) , Brisbane, Australia. He also holds the titles of Professor of Tropical Health, University of Queensland (UQ) and Professor, Griffith University in Brisbane. He obtained his higher degrees from the University of Wales, United Kingdom, and, following academic positions at Imperial College, London, he moved to Brisbane in 1989 to become Research Coordinator of an Australian government-funded Tropical Health Program, a joint consortium between QIMR and THP.

His laboratory focuses on understanding the biology and pathogenesis of parasitic worms of humans, particularly schistosoma bloodflukes and the hydatid (Echinococcus) tapeworms, and on developing new interventions (particularly vaccines) and diagnostic procedures against these pathogens that will aid in their elimination. He has held the position of Vice-President of the World Federation of Parasitologists. He is a member of the Asia-Pacific International Molecular Biology Network, and he has been an appointed member of the WHO Steering Committee on Schistosomiasis since 2000. He sits on the editorial boards of eleven international journals,  has received numerous invitations to present his research at national and international fora, and has published more than 340 articles, 2 books, and 17 book chapters in his career to date.

HYPOTHESIS

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Hypotheses:
The pattern and regulation of Th1 and Th2 cytokine production correlate with schistosome-induced granuloma formation and dictate the progression to advanced human disease, typified by periportal fibrosis and portal hypertension. IL-13-dependent signaling pathways influence the development of schistosome-induced fibrosis, portal hypertension and hepatosplenic disease.

Goals:
There is solid evidence in mice for a central role for Th2 pro-fibrotic type cytokine regulation in schistosome egg-induced granuloma formation and severe hepatic hepatosplenic disease. However, the contribution of Th1 and Th2 associated cytokines to this process in human schistosomiasis relies on indirect evidence that is unclear and speculative. This project will investigate directly the cytokine-mediated mechanisms that influence fibrogenesis and granuloma formation and regulate progression to the severe forms of chronic schistosomiasis using surgically removed target tissues (spleen, liver) from a large Chinese cohort of patients and controls.

Methods:
The approach we will take is novel, and results from a new Chinese initiative for the clinical management of severe cases of schistosomiasis involving surgical removal of the spleen to ameliorate the effects of advanced disease. This has resulted in our having access to the removed spleen tissue and wedge liver biopsy material, collected at the same time as surgery, from a large cohort of patients with varying degrees of hepatic fibrosis grading (I-III) for analysis. In addition, we have collected splenic and liver samples from uninfected controls and samples from subjects with long-standing infections but relatively low grade-pathology, and from others in the early stages of disease for direct comparison. Spleen tissues and wedge liver biopsies will be compared in cases and controls by fibrosis grading, histology, immunohistochemistry and RT-PCR analysis of Th1- and Th2-cytokines, chemokines, fibrosis and collagen synthesis or degradation markers directly in the tissue samples and in supernatants obtained from schistosome antigen-stimulated splenocyte lymphoproliferation assays. In addition, RNA from the spleen and liver samples will be used to probe human-tissue-specific microarrays to compare differential gene expression profiles in the cases and controls so as to further explore the mechanisms involved in fibrogenesis, collagen deposition, granuloma formation, and the progression to hepatosplenic disease.