Filifactor alocis interactions with neutrophils

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Abstract Periodontitis is a microbial-induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. With the development of high-throughput sequencing technologies, and their application to the oral microbiota, several newly appreciated organisms have become recognized as associated with periodontal lesions. Among these is the Gram-positive anaerobic rod Filifactor alocis which is present in high numbers in periodontal disease sites compared to healthy sites. However, association does not establish causality, and the challenge now is to determine the potential pathogenicity of F. alocis. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. Neutrophils are a major component of the innate host response and the outcome of the interaction between periodontal pathogens and neutrophils is a key determinant of oral health status. An understanding of both microbial and host factors is therefore essential to increase our knowledge of the periodontal disease process. The current proposal will test the hypothesis that Filifactor alocis modulates neutrophil functional responses as an immune evasion strategy to avoid killing and promote inflammation. We will test our hypothesis by the following specific aims: Aim 1: To characterize neutrophil respiratory burst response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis stimulation causes dysfunction of select neutrophil responses, and thus compromises bacterial killing. Aim 2: To characterize the neutrophil oxygen-independent antimicrobial response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis will modulate neutrophil degranulation and thus subvert neutrophil antimicrobial mechanisms. Aim 3: To determine the effect of F. alocis on neutrophil recruitment and activation in an animal model. The goal of this aim will be to test the hypothesis that F. alocis infection will stimulate neutrophil recruitment, activation, and matrix metalloproteinases release to promote inflammation in vivo. The current project is a collaborative effort from a new/early stage investigator with expertise in neutrophil biology and inflammation (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong framework to study the interaction between F. alocis and neutrophils. Furthermore, the data generated from this application are a necessary component of the information that will be required to allow the development of novel therapeutic strategies for controlling periodontal disease.