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，在美国影响约50%的成年人。 USA.牙周炎的病因学与微生物组成的变化和 从原生共生群落的密度到更多样化的生态失调微生物群落。高通量 应用测序技术来表征牙周微生物群的组成， 疾病部位，揭示了大量新认识的口腔病原体的存在。其中， 革兰氏阳性厌氧杆菌Filifactoralocis，在牙周病的口腔生物膜中大量存在 与健康网站相比。现在的挑战是确定潜在的致病性， 机制和可能的免疫颠覆武器库。alocis。主机装载到 细菌攻击在疾病进展中起主要作用。中性粒细胞是主要的白细胞， 龈下裂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 status.了解宿主如何应对不同的微生物挑战将增加我们的知识 疾病的过程。目前的建议将测试的假设，F。Alocis破坏中性粒细胞效应子 以促进其生存。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。 嗜中性粒细胞囊泡运输的alocis调节，以逃避杀死并促进细菌定植和骨形成 损失这个目标的目标将是测试的假设，F。alocis操纵中性粒细胞信号通路 将杀菌活性从炎症反应中分离出来，成功地逃避了杀戮。目标2： 描述F. alocis调节人中性粒细胞凋亡的能力。这一目标的目标将是测试 假设F. alocis调节中性粒细胞凋亡程序作为一种毒力策略， 嗜中性粒细胞吞噬体内的细胞内小生境。目前的项目是一个合作的努力， 研究者谁是在中性粒细胞生物学和炎症及其与新兴的相互作用领域的专家 口腔病原体（Uriarte博士）和口腔病原体和宿主细胞反应领域的专家， 牙周炎模型（拉蒙博士）。拟议的合作努力提供了一个创新和强有力的框架 为了解F. alocis。此外，此应用程序生成的数据将填充 我们的知识中的一个重大差距，并为开发新的治疗方法奠定基础， 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.