Genetic control of murine schistosomiasis: In search of genes

Infection 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 cytokine 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-gamma 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-1& beta; 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.