Filifactor alocis interactions with neutrophils

摘要 牙周炎是六种最常见的慢性炎症性疾病之一，在中国约50%的成年人受到影响 美国。牙周炎的病因与微生物组成和牙周炎的变化密切相关。 从土著共生群落到更多样化的非生物微生物群落的密度。高吞吐量 应用测序技术表征牙周微生物群的组成 疾病地点，显示存在大量新发现的口腔病原体。其中包括 牙周病口腔生物膜中大量存在革兰氏阳性厌氧菌纤毛因子 网站与健康网站的比较。现在的挑战是确定潜在的致病性、致病力 华南星的作用机制及可能的免疫颠覆库。主机装载到 细菌挑战在疾病进展中起着重要作用。中性粒细胞是招募的主要白细胞 龈下缝隙及其与微生物群落的相互作用是口腔健康的关键决定因素 状态。了解宿主如何应对不同的微生物挑战将增加我们的知识 疾病的进程。目前的提议将检验阿洛克斯菌破坏中性粒细胞效应器的假设。 促进其生存的功能。我们将通过以下具体目标来检验我们的假设：目标1：定义F. ALOCIS对中性粒细胞囊泡转运的调节以逃避杀菌和促进细菌定植和骨 损失。这一目标的目的将是检验阿洛克斯菌操纵中性粒细胞信号通路的假说。 将杀菌活性从炎症反应中解脱出来，成功逃脱杀戮。目标2：实现 表征阿洛克氏丝菌调节人中性粒细胞凋亡的能力。这个目标的目标将是测试 假设金黄色葡萄球菌作为一种毒力策略来调节中性粒细胞的凋亡程序，以保存 中性粒细胞吞噬小体内的细胞内壁龛。当前的项目是来自 研究人员，是中性粒细胞生物学和炎症及其与新兴疾病相互作用领域的专家 口腔病原体(乌里亚特博士)，口腔病原体和宿主细胞体内反应领域的专家 牙周炎模型(拉蒙特博士)拟议的合作努力提供了一个创新和强大的框架 研究阿洛克氏丝孢子菌的致病潜能。此外，此应用程序生成的数据将填充 我们在知识上的重大差距，并为开发新的治疗方法奠定了基础 对抗牙周炎。

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.