Filifactor alocis interactions with neutrophils

摘要牙周炎是一种由微生物引起的慢性炎症性疾病，影响支撑牙齿的牙龈组织。随着高通量测序技术的发展及其在口腔微生物群中的应用，一些新发现的微生物被认为与牙周病变有关。其中包括革兰氏阳性厌氧棒丝状因子，与健康部位相比，在牙周病部位大量存在。然而，关联并不能建立因果关系，现在的挑战是确定F. alocis的潜在致病性。慢性炎症性传染病如牙周炎可发生，因为病原体能够逃避或使先天免疫系统失效。中性粒细胞是先天宿主反应的主要组成部分，牙周病原体和中性粒细胞相互作用的结果是口腔健康状况的关键决定因素。因此，了解微生物和宿主因素对于增加我们对牙周病过程的认识至关重要。目前的提议将验证一种假设，即嗜中性粒细胞调节因子作为一种免疫逃避策略，以避免杀死和促进炎症。我们将通过以下具体目的来检验我们的假设：目的1：表征嗜中性粒细胞对F. alocis攻击的呼吸爆发反应。这个目的的目的是测试F. alocis刺激导致中性粒细胞选择性反应功能障碍的假设，从而损害细菌杀灭。目的2：表征嗜中性粒细胞氧不依赖的抗微生物反应，以应对嗜中性粒细胞嗜真菌的挑战。这一目的的目的将是测试的假设，f.a alocis将调节中性粒细胞脱颗粒，从而破坏中性粒细胞抗菌机制。目的3：在动物模型中确定嗜酸梭菌对中性粒细胞募集和激活的影响。本研究的目的是验证F. alocis感染会刺激中性粒细胞募集、激活和基质金属蛋白酶释放以促进体内炎症的假设。目前的项目是由一位具有中性粒细胞生物学和炎症专业知识的新/早期研究者（Uriarte博士）和一位口腔病原体和宿主细胞反应领域的专家（Lamont博士）合作完成的。提出的合作努力提供了一个创新和强大的框架来研究嗜中性粒细胞和F. alocis之间的相互作用。此外，从该应用程序产生的数据是信息的必要组成部分，将需要允许开发控制牙周病的新治疗策略。

DESCRIPTION (provided by applicant): 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.