Mechanisms and Immune consequences of atypical efferocytosis of neutrophils during Porphyromonas gingivalis infection.

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PROJECT SUMMARY/ABSTRACT Neutrophils recruited to the sites of bacterial infection or inflammation eventually undergo apoptosis and are cleared in situ by phagocytic cells such as macrophages. ‘Efferocytosis’ or the phagocytic uptake of apoptotic cells (AC), is a highly selective process that relies upon the recognition of apoptosis associated ligands, such as phosphatidylserine (PS), by efferocytic receptors on the engulfing cells. These interactions initiate downstream signaling that shuts down inflammatory pathways and orchestrates the hydrolytic breakdown of ACs within phagosomes/efferosomes for their eventual clearance. Several pathogens can manipulate efferocytosis in order to subvert immune clearance. We found that the periodontal pathogen Porphyromonas gingivalis uses a novel mechanism to dysregulate efferocytosis by causing the uptake of live neutrophils in a PS independent manner, possibly bypassing engagement and/or activation of PS binding efferocytic receptors. Our preliminary data show that this atypical efferocytosis of live cells resulted in sustained production of pro- inflammatory cytokines and a profound failure of macrophages to activate pro-resolution pathways. We hypothesize that P. gingivalis mediated atypical efferocytosis perpetuates inflammation in periodontal disease and breakdown of immune tolerance. In Aim 1 of this proposal, we will delineate specific signaling pathways that mechanistically link ingestion of live neutrophils to the generation of proinflammatory cytokines. In Aim 2 of this proposal, we will determine whether ingestion of live neutrophils results in degradation delays due to incomplete maturation of the efferosomes, resulting in diminished hydrolytic capacity. Defects in clearance of ACs within efferosomes is increasingly linked to chronic inflammation and autoinflammatory sequalae in a large number of diseases. Overall, the data generated from this grant will not only shed mechanistic insights atypical efferocytosis caused by a P. gingivalis but will also be useful in designing new therapeutic approaches to abate chronic inflammation associated with periodontitis. Furthermore, this application includes a comprehensive training plan that will enable me to strengthen my ability to define scientific questions and answer them using the strong technical skillset and conceptual understanding. I will continue to expand my expertise in areas of host-pathogen interactions, innate immune responses, and cellular signaling pathways and the knowledge and skill sets gained from the proposed training will be invaluable moving forward as I pursue a career as an independent investigator.