Involvement of dendritic cell Toll-like receptors in the innate response to Litomosoides sigmodontis infection and deviation by their Wolbachia endobacteria

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Filarial worm infections result in a mixed Th1/Th2 pro-inflammatory or a T regulatory (Tr-1) anti-inflammatory immune response, rather than the typical Th2 response seen to other worm infections. Confounding our understanding of the immune mechanisms is the presence of Wolbachia endosymbiotic bacteria in filariae, a second organism for stimulating the immune response. This laboratory has demonstrated that Wolbachia are sources of Toll-like receptor (TLR) 2 and 4 ligands. We have also shown that a ency in TLR4 leads to increased permissiveness to infection by the rodent filaria Litomosoides sigmodontis. A role for TLR is further suggested by our preliminary results with MyD88-/- mice, which have higher worm loads. Other preliminary results suggest dendritic cells (DC) are important for the innate response which controls filarial establishing. We aim to characterize how DC detect worms through TLR and to define the role of Wolbachia in the immune response by answering the following questions. What are the effects of TLR2, TLR4 and MyD88? How do filarial antigens affect the innate immune response through DC via TLR? Which organism (nematode, Wolbachia, or both) is the source of TLR antigen(s) which stimulate DC? The study would provide novel data on how innate responses via DC and TLR are induced against helminths, important knowledge for ultimate vaccine design.