TLR4 evasion, bacterial persistence and chronic inflammation

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DESCRIPTION (provided by applicant): Chronic inflammation results in significant host pathology and is associated with a number of diseases including autoimmune diseases, atherosclerosis, and infectious diseases. Porphyromonas gingivalis is a low- abundance oral bacterium linked to the initiation and progression of inflammatory oral bone loss and to other chronic inflammatory systemic diseases. The overall goal of this Project is to define the mechanisms by which P. gingivalis evades TLR4 signaling and manipulates autophagy to promote chronic inflammation. P. gingivalis has evolved mechanisms to evade TLR4 host immune detection through expression of a heterogeneous LPS lipid A species that functions as weak TLR4 agonist and strong TLR4 antagonist. In contrast to evasion of TLR4 signaling, P. gingivalis is a strong activator of TLR2 and utilizes a TLR2 mediated mechanism for intracellular entry into macrophages, which protects the organism from immune clearance via the intracellular degradative lysosomal pathway. A number of pathogens that evade lysosomal destruction infiltrate the autophagic pathway. Autophagy is also utilized for the secretion of the active form of IL-1??, a mediator of bacterial killing. We hypothesize that the ability of P. gingivalis to evade TLR4 signaling and to manipulate autophagy dampens IL-1? production and promotes survival in macrophages, resulting in chronic inflammation. Using relevant knockout mice and genetically modified P. gingivalis strains, we propose the following aims to test our hypothesis: Aim 1. To define the role of P. gingivalis mediated evasion of TLR4 signaling in monocytic cells in IL-1?? production and bacterial killing. Aim 2. To define the role of P. gingivais mediated manipulation of autophagy in monocytic cells in IL-1?? production and bacterial killing. Aim 3. To define the role of P. gingivalis mediated TLR4 evasion in monocytic cells on chronic inflammation in a murine model. Aim 4. To define the role of P. gingivalis mediated manipulation of autophagy in monocytic cells on chronic inflammation in a murine model.