Immuno-regulation of GI nematode infection

University Of Pennsylvania, Philadelphia PA

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Abstract

An estimated 2 billion people world-wide are infected with soil transmitted helminth parasites, with an estimated 300 million people suffering severe infections. The long term goals of this proposal are to gain a better understanding of the immuno-regulatory mechanisms that govern the initiation, regulation, and effector responses following gastrointestinal (GI) nematode infection. Trichuris muris is a natural GI nematode of mice and provides an immunologically well-defined model of human infection. Previous studies have shown that T helper type 1 (Thl) responses promote chronic infection, while Th2 responses are required for host protective immunity. However, the cellular and molecular mechanisms that control how T. muris is recognized by the innate immune system and how Th2 cytokines mediate expulsion of infection are unknown. Preliminary studies identified a critical role for NF-kappaB1 activation in immunity to T. muds. It is hypothesized that NF-kappaB1 regulates three novel pathways required for resistance to infection: (i) intestinal epithelial cells (IEC) activation; (ii) dendritic cell (DC) responses; and (iii) expression of RELMb, a novel immune effector molecule required for expulsion of GI nematodes. The requirements for these pathways in immunity to T. muds infection will be tested. First, the role of IEC and DC in innate recognition of T. muris and production of proinflammatory cytokines will be tested using either genetically manipulated animal hosts in which IEC function is specifically impaired, or the adoptive transfer of purified DC populations. Preliminary studies also identified a novel NF-kappaBl-dependent immune effector molecule, RELMb, that mediates expulsion of GI nematode infection. The factors that regulate expression of RELMb and mechanisms through which worms are expelled will be defined. Defining these pathways will provide new insights into the regulation of innate and adaptive Th2 responses in the GI tract and offer novel targets to manipulate anti-nematode responses.