Filifactor alocis interactions with neutrophils

点击翻译按钮获取中文摘要

Abstract Periodontitis is one of the six most common chronic inflammatory diseases affecting ~ 50% of the adults in the USA. The etiology of periodontitis is strongly associated with changes in both the microbial composition and density of an indigenous symbiotic community to a more diverse dysbiotic microbial community. High-throughput sequencing techniques applied to characterize the composition of the periodontal microbiota obtained from disease sites, revealed the presence of high number of newly appreciated oral pathogens. Among these is the Gram-positive anaerobic rod Filifactor alocis, present in high numbers in the oral biofilm of periodontal disease sites compared to healthy sites. The challenge now is to determine the potential pathogenicity, virulence mechanisms and possible immune subversion arsenal of F. alocis. The response that the host mounts to the bacterial challenge plays a major role in disease progression. Neutrophils are the primary leukocyte recruited to the subgingival crevice and their interaction with the microbial community is a key determinant of oral health status. Understanding how the host responds to the different microbial challenges will increase our knowledge of the disease process. The current proposal will test the hypothesis that F. alocis undermines neutrophil effector functions to promote its survival. We will test our hypothesis by the following specific aims: Aim 1: To define F. alocis regulation of neutrophil vesicular trafficking to evade killing and promote bacteria colonization and bone loss. The goal of this aim will be to test the hypothesis that F. alocis manipulates neutrophil signaling pathways to uncouple the bactericidal activity from the inflammatory response to successfully evade killing. Aim 2: To characterize F. alocis ability to modulate apoptosis in human neutrophils. The goal of this aim will be to test the hypothesis that F. alocis modulates neutrophils apoptotic program as a virulence strategy to preserve an intracellular niche within the neutrophil phagosome. The current project is a collaborative effort from an investigator who is an expert in the field of neutrophil biology and inflammation and its interactions with emerging oral pathogens (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses using in vivo models of periodontitis (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong framework to characterize the pathogenic potential of F. alocis. In addition, the data generated from this application will fill a significant gap in our knowledge and lay the foundation for development of new therapeutic approaches to combat periodontitis.