Severe Schistosomiasis: Progress in Understanding Iimmune Response
Apr 17, 2014 - 12:14:51 PM
Schistosomiasis makes some people very sick whereas others tolerate it relatively well, and no one knows precisely why. To answer this question, Miguel Stadecker, M.D., Ph.D., professor in the Department of Integrative Physiology & Pathobiology at Tufts University School of Medicine, uses mouse strains that similarly develop severe or mild disease. He and Holly E. Ponichtera, graduate student in immunology at the Sackler School, discovered that an innate cell receptor called CD209a is linked to the development of T helper (Th) 17 cells, which can cause marked inflammation.
Th17 cells are part of the adaptive immune response, fighting certain disease-causing bacteria and fungi, but they are also implicated in the pathogenesis of autoimmune diseases. The Stadecker lab had previously reported that blocking Th17 cell function limits severe schistosomiasis.
"This is important," says Ponichtera, "because CD209a is a mouse equivalent of a molecule that in humans is called DC-SIGN, a lectin receptor on dendritic cells that senses a variety of pathogens, including the virus that causes AIDS. Regulating this molecule may prevent excessive unwanted inflammation, such as that seen in severe schistosomiasis."
Stadecker has been studying this disease since the 1980s, analyzing the host's immune response to the parasite eggs. His earlier work showed the importance of Th17 cells in understanding schistosomiasis. This type of T cell was present in larger quantities in mice with severe disease. He surmised that the Th17 cells also caused the severe inflammatory response seen in some patients.
In 2013, the laboratory's discovery of the role of Th17 cells was confirmed in the field when an international team of researchers tested blood samples from children in Senegal who were infected with schistosomiasis. The samples confirmed that Th17 cells were increased in patients with measurable pathology whereas, in infected individuals with no overt symptoms, the Th17 cells were offset by T regulatory cells that inhibit inflammation.
"We don't yet understand why mice that develop severe inflammation express about 20 times higher levels of CD209a than mice that do not develop severe disease, and we don't yet know about the role of DC-SIGN in human schistosomiasis. However, these cumulative results move us a bit closer to understanding why the disease manifestations can range from very few symptoms to death. Our studies might also have implications for diseases caused by other pathogenic helminths," said Stadecker, also a member of the also a member of the immunology program faculty at the Sackler School.
For more than 249 million people in the world, water is both a precious resource and a vehicle of disease. Fresh-water snails living in certain tropical regions of the world release the larval forms of the schistosome parasite, which penetrate the skin, migrate through the body, and develop into adults that lay eggs that cause the disease. While some people experience chronic infection with mild symptoms, about 10%, will develop severe inflammatory disease that can affect the gastrointestinal, urinary, and nervous systems, in some cases causing cancer or leading to death.
Although schistosomiasis is not contracted in the United States or Europe, the World Health Organization reports that this neglected tropical disease is endemic primarily in Africa, but is also found in South America, the Middle East, and Asia. Population migration has introduced schistosomiasis to new areas. Although effective drug treatment is available, re-infection is pervasive, and a vaccine is not available.
The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under awards R01AI018919 (MJS) and R01AI076575 (SCB). It was also supported by an NIH Director's New Innovator Award under award DP2OD002230 (NH); Canadian Institutes of Health Research under award MOP125933, and National Research Foundation of Korea-Global Research Network under award 2013S1A2A2035348 (both CC).
Additional authors are Mara G. Shainheit, Ph.D., postdoctoral scholar in Andrew Camilli's laboratory at Tufts University School of Medicine, and member of the NIH-funded Institutional Research Career and Academic Development Awards (IRACDA) Program, Training in Education and Critical Research Skills (TEACRS), at the Sackler School of Graduate Biomedical Sciences at Tufts; Beiyun C. Liu, Ph.D. student in the Medically-oriented Research in Graduate Education-Immunology (MERGE-ID) track program at the Sackler School; Raktima Raychowdhury, Ph.D., research associate at the Broad Institute of MIT and Harvard; Bridget M. Larkin, a Ph.D. student in immunology at the Sackler School; Joanne M. Russo, senior research technician in the Stephen Bunnell lab at TUSM; D. Brenda Salantes, former student of the Post-baccalaureate Research Education Program (PREP) in immunology at the Sackler School; Chao-Qiang Lai, Ph.D., research molecular biologist in the Nutrition and Genomic Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (USDA HNRCA); Laurence D. Parnell, Ph.D., computational biologist in the Nutrition and Genomic Laboratory at the USDA HNRCA; Tae J. Yun of the Institut de Recherches Cliniques de Montréal (Clinical Research Institute of Montreal) in Québec, Canada; Cheolho Cheong, Ph.D., director of the Cellular Physiology and Immunology research unit at the Institut de Recherches Cliniques de Montréal; Stephen C. Bunnell, Ph.D., associate professor of integrative physiology and pathobiology at TUSM and member of the immunology program faculty at the Sackler School; and Nir Hacohen, Ph.D., co-director of the Center for Cell Circuits at the Broad Institute.
Citation: Ponichtera et al., CD209a Expression on Dendritic Cells is Critical for the Development of Pathogenic Th17 Cell Responses in Murine Schistosomiasis. The Journal of Immunology, April 11, 2014, DOI: 10.4049/jimmunol.1400121
About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science.
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