Filifactor alocis interactions with neutrophils

描述(申请人提供)：牙周炎是一种由微生物引起的慢性炎症性疾病，影响支持牙齿的牙龈组织。随着高通量测序技术的发展及其在口腔微生物区系中的应用，一些新认识的微生物已被认为与牙周病变有关。其中之一是革兰氏阳性厌氧菌纤毛因子，与健康部位相比，在牙周疾病部位出现的数量较多。然而，相关性并不能确定因果关系，现在的挑战是确定阿洛克斯菌的潜在致病性。慢性炎症性传染病，如牙周炎，可能是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决定口腔健康状况的关键因素。因此，对微生物和宿主因素的了解对于增加我们对牙周病过程的了解是至关重要的。目前的提议将检验这样的假设，即Filifactor alocis作为一种免疫逃避策略来调节中性粒细胞的功能反应，以避免杀戮和促进炎症。我们将通过以下具体目标来验证我们的假设：目标1：表征中性粒细胞呼吸爆发对金黄色葡萄球菌攻击的反应。这一目标的目的将是检验这样一种假设，即刺激金黄色葡萄球菌会导致选定的中性粒细胞反应功能障碍，从而损害细菌杀灭。目的2：研究中性粒细胞对金黄色葡萄球菌攻击的氧非依赖性抗菌反应。这一目标的目的将是检验假设，即阿洛克氏杆菌将调节中性粒细胞脱颗粒，从而颠覆中性粒细胞的抗微生物机制。目的：在一个动物模型中，观察阿罗莫司对中性粒细胞募集和激活的影响。这一目标的目的将是检验这一假说，即白念珠菌感染将刺激中性粒细胞招募、激活和基质金属蛋白酶释放，以促进体内的炎症。目前的项目是一位在中性粒细胞生物学和炎症方面有专长的新的/早期研究员(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)共同努力的成果。拟议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嗜中性粒细胞之间的相互作用。此外，这项应用产生的数据是信息的必要组成部分，需要这些信息来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.