Genetic Control of Murine Schistosomiasis: In Search of Genes.
with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of
disease severity, both in humans and in an experimental mouse model. Severe disease is
characterized by pronounced hepatic egg-induced granulomatous inflammation in a
proinflammatory cytokine environment, while mild disease corresponds with reduced
hepatic inflammation in a Th2 skewed ... read morecytokine environment. This marked heterogeneity
indicates that differences in the host's genetic background significantly impact the
clinical outcome of schistosomiasis, yet little is known about the genetic basis of
dissimilar immunopathology and particularly the specific gene(s) that contribute to
disease severity. To investigate the role of genetic susceptibility in murine
schistosomiasis, we performed a QTL analysis on an F2 progeny derived from SJL/J and
C57BL/6 mice, which develop severe and mild pathology, respectively. QTL analysis
identified several genetic intervals controlling immunopathology as well as IL-17 and
IFN-γ production, including two loci, D4Mit203 and D17Mit82, which were highly
significantly linked to granuloma formation. Furthermore, A significant reduction of
hepatic granulomatous inflammation and IL-17 production in interval-specific congenic
mice demonstrated that these loci have a decisive effect on the development of
immunopathology in murine schistosomiasis. D4Mit203 was also identified as controlling
severe disease in a second genetic analysis between BL/6 and high pathology BL/10 mice.
Subsequent studies in these mice combining microarray analysis with an in vitro BMDC-CD4
T cell coculture system, demonstrated that enhanced immunopathology in BL/10 mice was
likely due to a defect in the alternative activation pathway of DCs. Further analysis of
candidate genes located within D4Mit203 provided strong evidence that G-CSFR is the
underlying causal gene. Finally, we investigated the schistosome infection in
wild-derived mouse strains, which possess a diverse gene pool likely to reveal novel
phenotypes of immune regulation. We now show that following infection, wild-derived MOLF
mice develop exacerbated immunopathology with high levels of IL-17 is controlled by a
locus in chr. 6, designated Why1, in which Irak2 mediates severe disease in a CD4 T cell
specific manner by enhancing IL-1β stimulation of Th17 cell development. The use
of wild-derived mice thus unravels IRAK-2 as a novel regulator of IL-1-induced
pathogenic Th17 cells in schistosomiasis. In sum, we identified several loci that
control both immunopathology and cytokine production during schistosome infection, and
provide strong evidence for the role of two genes, Csf3r and Irak2, that regulate the
development of severe disease.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Immunology.
Advisor: Miguel Stadecker.
Committee: Alexander Poltorak, Peter Brodeur, and Henry Wortis.
Keywords: Immunology, and Genetics.read less