Abstract
ABSTRACTYersinia pestis causes bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans. Plague develops as a consequence of bacterial neutralization of the host's innate immune response, which permits uncontrolled growth and causes the systemic hyperactivation of the inflammatory response. We previously found that host type I interferon (IFN) signaling is induced during Y. pestis infection and contributes to neutrophil depletion and disease. In this work, we show that type I IFN expression is derived from the recognition of intracellular Y. pestis by host Toll-like receptor 7 (TLR7). Type I IFN expression proceeded independent of myeloid differentiation factor 88 (MyD88), which is the only known signaling adaptor for TLR7, suggesting that a noncanonical mechanism occurs in Y. pestis-infected macrophages. In the murine plague model, TLR7 was a significant contributor to the expression of serum IFN-β, whereas MyD88 was not. Furthermore, like the type I IFN response, TLR7 contributed to the lethality of septicemic plague and was associated with the suppression of neutrophilic inflammation. In contrast, TLR7 was important for defense against disease in the lungs. Together, these data demonstrate that an atypical TLR7 signaling pathway contributes to type I IFN expression during Y. pestis infection and suggest that the TLR7-driven type I IFN response plays an important role in determining the outcome of plague.
Highlights
Yersinia pestis causes bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans
Toll-like receptor 7 (TLR7) is required for optimal expression of IFN- during Y. pestis infection of macrophages
To characterize the mechanism by which Y. pestis induces the expression of type I IFN, we measured the secretion of IFN- induced by T3SS-positive (T3SSϩ) and T3SS-negative (T3SSϪ) bacteria
Summary
TLR7 is required for optimal expression of IFN- during Y. pestis infection of macrophages. Similar results were observed when we compared IFN- secretion by macrophages infected with Y. pestis CO92 (T3SSϩ pgmϩ) and KIM6 (T3SSϪ pgm negative) (see Fig. S2A in the supplemental material) These data suggest that there could be differences in IFN- expression caused by infection by the two Y. pestis biovars Y. pestis bv. Consistent with the in vitro data, Myd88Ϫ/Ϫ mice challenged by intranasal infection with Y. pestis KIM D27 developed elevated serum IFN- levels, with no detectable differences compared to WT mice (Fig. 4D). These data are consistent with a critical role for a noncanonical, MyD88-independent TLR7 pathway in inducing IFN- expression during Y. pestis infection in vivo. The phenotypic observations suggest a bifunctional, tissue-specific role for TLR7 in the host response to Y. pestis CO92 infection
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