To assess the role of Toll-like receptor (TLR) signaling in host resistance to Mycobacterium avium infection, mice deficient in the TLR adaptor molecule Myeloid Differentiation Factor 88 (MyD88), as well as TLR2-/- and TLR4-/- animals, were infected with a virulent strain of M. avium and bacterial burdens and immune responses compared with those in wild type (WT) animals. MyD88-/- mice failed to control acute and chronic M. avium growth and succumbed 9 - 14 wks post-infection. Infected TLR2-/- mice also showed increased susceptibility, but displayed longer survival and lower bacterial burdens than MyD88-/- animals, while TLR4-/- mice were indistinguishable from their WT counterparts. Histopathological examination of MyD88-/- mice revealed massive destruction of lung tissue not present in WT, TLR2-/- or TLR4-/- mice. In addition, in vivo TNF, IL-12p40 mRNA induction and IFN-gamma cytokine synthesis were impaired in the infected MyD88-/- mice but not in the other strains. These findings indicate that resistance to mycobacterial infection is regulated by multiple MyD88-dependent signals in addition to those previously attributed to TLR2 or TLR4 and that these undefined elements play a major role in determining bacterial induced pro-inflammatory as well as IFN-gamma responses. We have previously shown that specific pathogen-free IL-10-deficient (IL-10 KO) mice develop a Th1-cytokine associated colitis after experimental infection with the intestinal bacteria Helicobacter hepaticus. This year we demonstrated that H. hepaticus Ag (SHelAg)-specific CD4+ Th1 clones transfer disease to H. hepaticusinfected T cell-deficient RAG KO hosts. Importantly, uninfected recipients of the SHelAgspecific clones did not develop intestinal inflammation, and an unrelated control Th1 clone did not induce colitis upon transfer to infected RAG KO mice. The disease-inducing T cell clones recognized antigen(s) (Ag) specifically expressed by H. hepaticus and other murine Helicobacter species but failed to respond to Ag preparations from H. pylori, various non-Helicobacter bacteria, or with cecal bacterial lysate from uninfected mice. Characterization of the Ag specificity of one of the clones showed that it reacts uniquely with a 15-mer peptide epitope on the flagellar hook protein (FlgE) of H. hepaticus . Together, these results demonstrate that colitis can be induced by clonal T cell populations that are highly specific for target Ag on intestinal bacteria, suggesting that an aberrant T cell response directed against gut flora is sufficient to trigger IBD.
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