Immunological Intervention In Schistosomiasis

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Abstract

The purpose of our research program is to elucidate the mechanisms of vaccine-induced immunity in schistosomiasis and to better understand the pathogenesis of the disease. Transgenic and knockout mice are employed in these studies so that basic pathogenic processes can be investigated. Key findings from our murine studies are then extended to the field, where the immune responses of schistosomiasis patients exhibiting different clinical forms of the disease are examined. The ultimate goal of this research is to understand the host immune response to infection so that immunologically based strategies might be employed in the development of a highly effective vaccine for schistosomiasis. Progress was achieved in the following areas during the year: 1) the pro-fibrotic activity of IL-13 was investigated in further detail: studies showed that the fibrotic mechanism induced by IL-13 is unrelated to tissue eosinophil or mast cell responses, but does correlate with the patterns of IL-13, IL-10, and interferon gamma (IFN-gamma) production. Indeed, severe fibrosis correlated with a high IL-13 and low IFN-gamma/IL-10 mRNA responses. Importantly, studies showed that the progression of established fibrosis is reversible by IL-13 blockade. 2) Patterns of chemokine expression were investigated in models of Schistosoma mansoni inflammation and infection and relationships between Type 1 and Type 2 responses and chemokines were evaluated in vivo. 3) Mouse cDNA microarrays were used to molecularly phenotype the gene expression patterns that characterize two disparate but equally lethal forms of liver pathology, which develop in Schistosoma mansoni infected mice polarized for type-1 and type-2 cytokine responses. 4) A novel schistosome protein, S. mansoni rhodopsin (SmRHO), was cloned and identified as the first molecularly characterized GPCR described in schistosomes. Sequence analysis revealed that SmRHO shares extensive phylogenetic conservation among rhodopsins/opsins expressed in water-dwelling invertebrates. We showed that SmRHO is expressed in the free-living, light responsive miracidia and cercaria stages and is down-regulated in the adult, vertebrate residing forms. Importantly, this information can now be used to search for additional parasite encoded GPCR super-family members, which may be associated with chemoreception, chemotaxis, and olfaction.