MAPK phosphatases and innate immunity

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DESCRIPTION (provided by applicant): Mitogen activated protein kinase (MAPK) signaling cascades play an integral role in mediating the host innate immune response to infection. Regulation of these signaling pathways is tightly controlled by mitogen activated protein phosphatases (MAPs) that ensure appropriate levels of response to infection. For example, mice impaired in expression of individual mammalian MAPs exhibit loss of regulation of immune responses resulting in severe inflammation and sepsis in response to infections. Recent work from my laboratory and others has resulted in the discovery of a novel class of bacterial effectors including Shigella OspF and Salmonella MkfI that are bacterial MAPs. We have preliminary data that OspF and MkfI differentially inactivate MAPK signaling cascades during infections. OspF selectively dephosphorylates ERK and p38 MAPK while MkfI dephosphorylates ERK, p38 and SAP/JNK. Based on these observations we hypothesize that bacterial pathogens differentially modulate the host innate immune response by selectively inactivating MAPK signaling cascades and that this differential signaling results in alterations in the secretion of host cell cytokines. Furthermore we hypothesize that inhibition of bacterial MAPs by small molecules will provide new avenues for the development of antimicrobial agents that act by boosting the host innate immune response. Although the following experiments in this proposal are focused on the OspF family of MAPs, these studies will likely result in important insights into the mechanisms of regulation of host innate immunity by other bacterial pathogens that also inactivate host MAPK signaling pathways including Yersinia species and Bacillus anthracis. PUBLIC HEALTH RELEVANCE: Many bacterial pathogens like Shigella inject proteins that disarm the host immune response. This proposal will investigate the mechanism used by one of these proteins, OspF, to suppress the host innate immune response. The proposal will also investigate whether drugs that inhibit OspF might provide a new way to treat infections by boosting the hosts own immune response.