Numerous pathogens grow inside host cells. During the intracellular stage of infection, pathogen proteins establish intricate interactions with host proteins to hijack their cellular machinery. The bacterium Shigella flexneri thrives in the cytoplasm of human intestinal epithelial cells. To do so this bacterium must inject proteins that are dubbed effectors before and after cell invasion. IpaH are an uncommonly large family of effectors, comprising 9 members, for example, in S. flexneri 5. These proteins are hypothesized to interfere with normal cellular function by deregulating their degradation by the ubiquitin-proteasome system. Although IpaH9.8 has been implicated in dampening the innate immune response, diversity in the putative substrate binding domain across the IpaH family indicates that there might be other targets. Thus, the primary objectives of this project are: 1) perform a spatio-temporal study of the transcription, injection and sub cellular localization of IpaH effectors inside infected cell; 2) track the host cell protein targeted to the proteasome by the IpaH. In the frame of this project, I will develop a multidisciplinary strategy to study host-pathogen interactions by combining proteomics and cell biology approaches, pathophysiologic models of Shigellosis and computer simulations.
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