Despite considerable recent progress in research on regulation of immune responses to nematode infections and extensive descriptions of the physiologic and inflammatory changes in the intestine of parasitized individuals, current understanding of the mechanisms of anti-nematode immunity remains limited. One cause for this deficiency has been a failure to integrate an understanding of parasite biology with knowledge of the immune response. Such an integrated approach, as described in this proposal, will produce new knowledge that will facilitate development of treatments and vaccines against intestinal pathogens. Our long range goal is to elucidate the ways by which the host's immune response interferes will parasitism by nematodes, leading to clearance and immunity. Trichinella spiralis initiates infection in a susceptible host when it invades and then travels through intestinal epithelial cells. The P.I. hypothesizes that the processes of invasion and intercellular transit are facilitated by glycoproteins that are disgorged by infectious larvae. These glycoproteins bear complex glycans that are capped with a novel sugar, called tyvelose. The investigator has shown that antibodies able to bind tyvelose protect epithelia from invasion and cause established T. spiralis larvae to abandon their niche. In this proposal, the aim is to investigate the molecular basis for establishment of the epithelial niche of T. spiralis, and to elucidate the mechanism of interference by protective antibodies.
The specific aims are formulated as the following questions: 1) How do tyvelose-specific IgG antibodies interfere with parasite entry into or movement through epithelial cells? 2) How do T. spiralis glycoproteins interact with host cells to facilitate parasitism? 3) How does the host cell participate in the process of nematode invasion? The experimental approach will rely heavily on a new tool that investigator developed during the previous funding period. She has shown for the first time that cultured epithelial cell lines are susceptible to invasion by T. spiralis. This assay allows her to study the processes or invasion, niche establishment and expulsion under conditions that can be carefully controlled and readily manipulated. She plans to apply this assay in an interdisciplinary. She plans to apply this assay in an interdisciplinary approach in the investigation of parasitism and immunity against intestinal nematodes.
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