A role for immune cell plasticity in commensal survival and escalation of inflammation

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Project Summary/Abstract Oral commensal microbes, including oral streptococci, are increasingly recognized as an essential component in the development of periodontal disease. Commensals contribute to the recruitment and growth of keystone disease-initiating microbes and are part of the dysbiotic disease-associated microbiome. Innate immune phagocytes, including macrophages, also play an essential role in the development of periodontal disease, and phagocytes themselves are phenotypically diverse. Interactions between phagocytes and keystone pathogens are well studied. However, relatively little is understood of the interactions between phagocytes and commensal streptococci. Also unknown is how an initial immune disruption by keystone pathogens can alter host immune interactions with oral streptococci that may enhance the latter’s contribution to disease. We have data highlighting a novel, yet counterintuitive, relationship between macrophages and S. gordonii: the bacterium is better able survive within, and promote enhanced cytokine release from, inflammatory macrophages. This new data, along with the knowledge that active periodontitis lesions have an increase in inflammatory macrophages leads us to our central hypothesis that upon initiation of inflammation, changes in macrophage-oral streptococci interactions allow the normally commensal bacterium to increase resistance to destruction and leads to enhanced cytokine production and inflammation. We will test our hypothesis by 1) assessing the molecular details of phagosomal escape and subsequent inflammatory promotion of S. gordonii within phagocytes, 2) determine the mechanisms of S. gordonii inflammatory modulation of macrophages initially activated by the keystone pathogen P. gingivalis and 3) begin to examine the in vivo mechanisms of increased S. gordonii survival within inflammatory macrophages. The overall aim of this research is to increase our understanding of the consequences of changes in host- commensal interactions upon initiation of inflammation. The rationale is that with an increased understanding of the conditions and molecular mechanisms by which commensals can act as pathobionts, we will achieve a first step in the long-term goal of developing new targets and strategies for the prevention and treatment of oral bacterial-associated inflammatory diseases.