平特五不中

Event

Guest Speaker, Dr. Felix Yarovinsky-Excellence in Genetics & Immunology Seminar Series

Monday, November 29, 2010 15:30to16:30
McIntyre Medical Building 3655 promenade Sir William Osler, Montreal, QC, H3G 1Y6, CA

Toll-like receptors (TLRs) play important roles in sensing and directing immune responses to viral and microbial pathogens. We examined the mechanism by which TLRs contribute to host defense against the lethal intracellular pathogens Toxoplasma gondii and Francisella tularensis by using mice selectively lacking the key TLR signaling protein MyD88 in different innate immune cell types. Lack of MyD88 in dendritic cells (DCs), but not in macrophages or neutrophils, resulted in high susceptibility to infection with T. gondii. In the mice deficient in MyD88 in DCs, the early IL-12 response by DCs was ablated, the IFN-g response by natural killer cells was delayed, and the recruited inflammatory monocytes were incapable of killing the T. gondii parasites. The T cell response, although attenuated in these mice, was sufficient to eradicate the parasite during the chronic stage, provided that defects in DC activation were compensated by IL-12 treatment. These results demonstrate an unappreciated central role of DCs in orchestrating the innate immune response to an intracellular parasite and establish that defects in pathogen recognition by DCs predetermine sensitivity to infection. A remarkable corollary of our findings is that the innate recognition of T. pathogens by DCs predetermines the outcome of the chronic phase of the infection independently of the status of T cell activation. That is, if the type 1 innate immunity fails to contain the infection adequately while adaptive immunity is being induced, the resulting greater burden of parasites cannot be adequately controlled by T cell immunity without lethality in the chronic phase.

A similar defensive pathway also appeared to be employed against the intracellular bacterial pathogen Francisella tularensis, suggesting a general role for TLR signaling in DC for regulation of innate immune responses to intracellular pathogens.

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