Bacterial flagellins are unusual microbial products that can be directly recognized by receptors of both the innate and adaptive immune system. Since flagellins initiate an innate immune response, they have the potential to function as molecularly defined adjuvants, and are being studied in preclinical vaccine studies. Expanding our knowledge about the innate immune response to bacterial flagellins is important for understanding immunity to flagellated pathogens and has the additional potential to influence future vaccine and adjuvant development. Mucosal dendritic cells (DC) are the only hematopoietic population known to constitutively express the flagellin receptor, TLR5. The effect of bacterial flagellins on intestinal DC antigen presentation and migration have not previously been examined but have the potential to influence bacterial pathogenesis and host immunity. Our overall hypothesis is that Salmonella flagellin recognition by intestinal DCs enhances the presentation of flagellin epitopes and initiates rapid intestinal DC migration. We expect the rapid response of TLR5'DCs is beneficial to host immunity but is also beneficial to the bacteria since it enables efficient pathogen dissemination. It is not known if TLR5 ligation on intestinal DCs can influence the presentation of flagellin peptides on surface MHC molecules. Our working hypothesis in Specific Aim 1 is that activation of intestinal DCs via TLR5 preferentially enhances the display of flagellin peptides on surface MHC molecules. This hypothesis predicts a direct link between surface TLR ligation and subsequent antigen presentation, and could explain the notable dominance of flagellin-specific T cell responses in infectious and inflammatory diseases of the intestine. We propose to examine this hypothesis using new reagents that we have developed to directly track presentation of flagellin epitopes on antigen presenting cells in vitro and in vivo. Reports suggest that Salmonella provoke rapid migration of an unusual DC population in the intestinal lamina propria to enter the host. However, the bacterial stimulus provoking these early DC migration events are undefined. Our hypothesis in Specific Aim 2 is that recognition of bacterial flagellins causes rapid DC migration in the intestine. We propose to examine this hypothesis using reagents that will allow us to physically track DC migration from the lamina propria.
Typhoid is an infectious disease that kills over 600,000 people per year in developing countries and is recognized as a potential bioterrorist threat in the US. This proposal aims to understand the interaction of a major bacterial protein, flagellin, with the infected host and particularly examine how this protein affects bacterial pathogenesis and innate immunity. This proposal has the potential to expand our understanding of pathogen-host interactions during typhoid.
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