P. gingivalis Mediated Evasion Strategies

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DESCRIPTION (provided by applicant): A number of successful pathogens have evolved mechanisms to evade host defense, thus establishing persistent and chronic infections. A hallmark of chronic infection with the oral pathogen, Porphyromonas gingivalis, is the induction of a chronic inflammatory response. Although membrane- bound innate immune receptors, including Toll-like receptors (TLR), play a role in inflammation in response to P. gingivalis, it i unknown how intracellular host defense mechanisms to this pathogen contribute to persistent infection and resulting in chronic inflammation. We have recently reported on a novel strategy by which P. gingivalis modulates the levels of key intracellular proteins involved in cell death and host defense responses. We demonstrate that the lysine-specific bacterial cysteine protease of P. gingivalis (gingipain K - Kgp) induces the proteolysis of receptor interacting protein kinase 1 (RIPK1) and RIPK2. Our preliminary studies reveal functional consequences of P. gingivalis mediated RIPK degradation on intracellular immune signaling responses. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation. Given the roles of RIPK in TNF-R induced cell activation and sensing of intracellular pathogens, we propose the ability of P. gingivalis to transiently degrade RIPK functions as a mechanism to avoid intracellular innate immune signaling and allows for bacterial persistence within target cells. The following specific Aims will test this hypothesis: Aim 1. To define the functional consequences of Kgp-mediated RIPK degradation on innate immune signaling and bacterial persistence; Aim 2. To characterize the ability of RIPK cleaved products to function in inhibition of NF?B activation; Aim 3. To assess the efficiency of gingipain inhibitos on the inhibition of P. gingivalis-induced chronic inflammation at local sites in a murine model; and Aim 4. To assess the efficiency of gingipain inhibitors on the inhibition of P. gingivalis-induced chronic inflammation at systemic sites in an ApoE-/- murine model. The ability to specifically block Kgp-mediated modification of cellular kinases represents a novel strategy to target bacterial persistence and innate immune signaling within host cells. Successful undertaking of the proposed studies has the potential to identify and validate novel therapeutic interventions that target pathogen evasion mechanisms associated with chronic infection and the resulting inflammatory sequelae.