Schistosomiasis is a major neglected helminthic disease suffered by over 200 million people throughout the world. Critical to understanding schistosomiasis is the notion that it represents an immunologically mediated disease, that is, the damage to the affected tissues is inflicted by the host's own immune system, rather than by the parasite itself. Thus, morbidity and mortality are largely due to a pathogenic CD4 T lymphocyte-mediated immune response against parasite egg antigens. This results in granulomatous and fibrosing inflammation, which in the case of the species Schistosoma mansoni, takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual. In the majority of cases there is relatively limited immunopathology with good survival, however, in a minority of patients there is severe disease and death. S. mansoni infection in a mouse model similarly results in marked strain variation of immunopathology. In CBA mice, severe hepatic inflammation is associated a novel subset of pathogenic CD4 T cells producing IL-17 (Th17 cells), of which an expanded, clonally-restricted subpopulation is specific for the immunodominant epitope 234-246 of the major Sm-p40 schistosome egg antigen (Sm-p40234-246). In contrast, C57BL/6 mice develop milder lesions within the context of a largely anti-inflammatory immune response. The objective of the present application is to investigate the mechanisms that underlie the development of the severe form of immunopathology embracing the hypothesis that this is precipitated by a distinct, genetically determined innate antigen-presenting cell (APC) reaction to parasite products resulting in the development of a pathogenic adaptive Th17 cell response.
Aim 1 of the proposal is to ascertain by gene profiling, and functionally test by gene knock- down, the lectin receptors on APC that recognize specific parasite egg-derived glycoproteins leading to pathogenic Th17 cell differentiation in CBA mice.
Aim 2 is to understand the role of Sm-p40-reactive T cells in mediating severe pathology by making use of novel mice expressing a transgenic Sm-p40-specific T cell receptor, or rendered unresponsive to Sm-p40 by virtue of transgenic expression of this antigen in the thymus.
Aim 3 is a forward genetic analysis to identify relevant quantitative trait loci taking advantage of unique congenic strains between BL/10 and BL/6 mice, which differ in only 5% of their genome, and yet exhibit significantly dissimilar IL-17 production and hepatic egg-induced inflammation. The proposed studies will provide new insights into the mechanisms leading to severe immunopathology in schistosomiasis. Their ultimate objective is the design of focused, realistic and practical strategies for amelioration of disease, which could be amenable for consideration and implementation in the human patient population.

Public Health Relevance

Schistosomiasis is a major parasitic disease caused by trematode helminths which in its severe form can lead to death in genetically predisposed individuals. Severe disease is largely a consequence of an over- zealous host immune response against the parasite eggs. Using a well-established mouse model and state-of-the-art technology, the studies in this proposal are designed to better understand the mechanisms that lead to severe disease, with the ultimate purpose of implementing immuno-interventions that will benefit those most gravely afflicted or known to be at risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018919-27
Application #
8678813
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1995-09-30
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
27
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Smith, Patrick M; Sproule, Thomas J; Philip, Vivek M et al. (2015) Minor genomic differences between related B6 and B10 mice affect severity of schistosome infection by governing the mode of dendritic cell activation. Eur J Immunol 45:2312-23
Ponichtera, Holly E; Stadecker, Miguel J (2015) Dendritic cell expression of the C-type lectin receptor CD209a: A novel innate parasite-sensing mechanism inducing Th17 cells that drive severe immunopathology in murine schistosome infection. Exp Parasitol 158:42-7
Ponichtera, Holly E; Shainheit, Mara G; Liu, Beiyun C et al. (2014) CD209a expression on dendritic cells is critical for the development of pathogenic Th17 cell responses in murine schistosomiasis. J Immunol 192:4655-65
Liberman, Rachel; Bond, Sarah; Shainheit, Mara G et al. (2014) Regulated assembly of vacuolar ATPase is increased during cluster disruption-induced maturation of dendritic cells through a phosphatidylinositol 3-kinase/mTOR-dependent pathway. J Biol Chem 289:1355-63
Mbow, Moustapha; Larkin, Bridget M; Meurs, Lynn et al. (2013) T-helper 17 cells are associated with pathology in human schistosomiasis. J Infect Dis 207:186-95
Kosinski, Karen C; Adjei, Michael N; Bosompem, Kwabena M et al. (2012) Effective control of Schistosoma haematobium infection in a Ghanaian community following installation of a water recreation area. PLoS Negl Trop Dis 6:e1709
Larkin, Bridget M; Smith, Patrick M; Ponichtera, Holly E et al. (2012) Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. Semin Immunopathol 34:873-88
Stadecker, Miguel J (2012) The gamut of host immune responses and immunopathology in parasitic diseases caused by protozoa and helminths: human perspective and experimental models. Semin Immunopathol 34:733-4
Smith, Patrick M; Jacque, Berri; Conner, James R et al. (2011) IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection. PLoS Pathog 7:e1002272
Shainheit, Mara G; Lasocki, Krzysztof W; Finger, Eduardo et al. (2011) The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β. J Immunol 187:5328-35

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