Deregulation of Toll-like receptor-controlled life and death signals by Yersinia

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The response of innate immune cells to microbial infection is controlled by complex regulatory pathways. A host cell compromised by a microbe may signal inflammation and survive, or undergo cell death with different outcome. The cellular mechanisms that govern the activation of the distinct reactions are, however, poorly defined. Our previous results have shown that the gram-negative enteropathogenic bacterium Y. enterocolitica targets Toll-like receptor (TLR)-induced signaling pathways to trigger apoptosis in macrophages. TLRs are central sensors of microbial infection that elicit inflammation, but they may also signal different forms of cellular death. We want to use Yersinia as tool to dissect the signals of life and death downstream from TLR4 in infected macrophages. For this purpose, the molecular mechanisms by which Yersinia virulence proteins alter structure, function and recruitment of RIP1 and MyD88, two central adapter proteins within the TLR signaling cascade, will be characterized. This aims to specify the regulatory paths that dictate the switch from cell survival to controlled apoptosis and necrosis in macrophages upon microbial challenge. A better understanding of the signaling networks of programmed death in the innate immune response could provide a basis for the development of cell death-inducing or -modulating drugs that may influence host immunity, but also tissue homeostasis and tumorigenesis.