Regulation of Oral Bacteria by Pattern Recognition Receptors

模式识别受体对口腔细菌的调节

• 批准号: 8024557
• 负责人: NAOHIRO INOHARA
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024557
• 关键词: Adult; Affect; Anti-Bacterial Agents; Antibacterial Response; Bacteria; Biochemical Genetics; Cell Line; Cells; Communities; Complex; Data; Defense Mechanisms; Defensins; Dental caries; Development; Disease; Endocarditis; Epithelial Cells; Exhibits; Gingiva; Goals; Homeostasis; Human; Immune; Immune response; Immune system; Infection; Lead; Link; Maintenance; Mediating; Microbe; Microbial Biofilms; Mouth Diseases; Mus; Oral; Oral cavity; Oral mucous membrane structure; Organism; Outcome Study; Pattern recognition receptor; Peptides; Periodontitis; Population; Porphyromonas gingivalis; Predisposition; Production; Prosthesis; Proteins; Receptor Signaling; Regulation; Role; Streptococcus mutans; Testing; Tissues; Toll-like receptors; Tongue; Tooth Diseases; Wild Type Mouse; antimicrobial; antimicrobial peptide; commensal microbes; human disease; improved; in vivo; insight; microbial; microbial host; novel; oral bacteria; oral commensal; oral pathogen; pathogenic bacteria; prevent; receptor; receptor-mediated signaling; tooth surface

DESCRIPTION (provided by applicant): Host recognition of bacteria by specific pattern-recognition receptors (PRRs), including Nod proteins and Toll-like receptors (TLRs), initiates antibacterial defense mechanisms and modulates the homeostasis of host-bacterial interactions. The deficiency of immune recognition results in high susceptibility of the host to infection by pathogenic bacteria. The oral cavity harbors an abundant and diverse community of bacteria, some of which have been implicated as etiological agents of common diseases such as dental caries and periodontitis. Epithelial cells lining the oral cavity and gingival tissue are known to be involved in immune responses against bacterial challenge including the production of antimicrobial peptides. However, the mechanisms by which host cells detect oral bacteria and induce antibacterial responses are largely unknown. The goal of this proposal is to test the hypothesis that Nod proteins and TLRs sense and regulate the development and maintenance of the oral microflora and the immune response to pathogenic bacteria including P. gingivalis. Preliminary results demonstrate that mice lacking PRR signaling contains oral microflora different from that of wild-type mice, suggesting that PRRs mediate selective elimination of commensal and/or pathogenic bacteria. We find that the activity of bacteria to stimulate Nod/TLR is highly diverse among bacterial species with commensal bacteria exhibiting low stimulatory activity. Thus, we hypothesize that PRRs, specifically Nod1/ Nod2, affect microflora development and pathogenic bacteria in oral cavity through host immune responses. Furthermore, we hypothesize that the oral microflora controls the susceptilibity of the host to P. gingivalis via PRR signaling. In this proposal, we propose biochemical and genetic studies to test our hypotheses and to understand the role of PRRs in the regulation of oral microflora development. These studies will provide novel insight into the mechanisms that govern the susceptibility of the host to infection by oral pathogens which may lead to the development of novel therapies for oral diseases.The human oral cavity has a complex, diverse and dynamic microflora harboring >700 cultivable and non-cultivable bacterial species. Oral bacteria colonize the surface of teeth, prostheses, gums and tongue by forming biofilm, an organized community of microbes in which microbial organisms highly interact with each other. Some bacteria are known to be involved in oral diseases; for example, Streptococcus mutans and related species in dental caries and Porphymonas gingivalis in adult periodontitis. In addition, oral bacteria have been also linked to other types of human disease including endocarditis. Oral bacteria are also involved in oral diseases through their interaction with pathogenic bacteria. Therefore, the current approach for dental diseases is not only to eliminate particular pathogenic bacteria, but also to promote bacterial populations that prevent colonization of pathogenic bacterial communities. However, the development of oral microflora in the normal state and oral diseases is largely unknown. Furthermore, studies on the control of microflora by host microbial sensing receptors have not been performed and thus the proposed studies will provide a novel concept about how hosts control the development and homeostasis of both beneficial and pathogenic microflora. The outcome of these studies is expected to provide novel insight not only into the interaction between microbial sensing receptors and commensal bacteria, but also into the role of host receptors and the microflora in periodontitis which is critical for the development of novel and improved therapies for the disease.

描述（由申请人提供）：特定模式识别受体（PRR）对细菌的识别，包括点头蛋白质和收费类受体（TLR），启动抗菌防御机制，并调节宿主 - 细菌相互作用的稳态。免疫识别的缺乏导致宿主对致病细菌感染的敏感性很高。口腔含有丰富而多样的细菌群落，其中一些被视为常见疾病的病因学药物，例如龋齿和牙周炎。众所周知，口腔内的上皮细胞和牙龈组织参与针对细菌挑战的免疫反应，包括产生抗菌肽。但是，宿主细胞检测口腔细菌和诱导抗菌反应的机制在很大程度上尚不清楚。该提案的目的是检验以下假设：点头蛋白质和TLR感知并调节口腔微生物的发育和维持以及对病原细菌（包括牙龈疟原虫）的免疫反应。初步结果表明，缺乏PRR信号传导的小鼠含有与野生型小鼠不同的口腔微生物，这表明PRR介导了选择性消除共生和/或致病性细菌。我们发现，在具有低刺激活性的共生细菌中，细菌刺激NOD/TLR的活性是高度多样的。因此，我们假设PRR（特别是NOD1/ NOD2）通过宿主免疫反应影响口腔中的微生物菌发育和致病细菌。此外，我们假设口腔菌群通过PRR信号来控制宿主对牙龈疟原虫的临时性。在此提案中，我们提出生化和遗传研究来检验我们的假设，并了解PRR在口腔微生物发育调节中的作用。这些研究将提供有关控制宿主对口腔病原体感染的敏感性的机制的新见解，这可能导致口腔疾病的新疗法发展。人口腔具有复杂，多样，动态的微生物含量> 700> 700可栽培和不可养殖的细菌种类。口服细菌通过形成生物膜（一个有组织的微生物社区，在其中微生物相互相互作用的微生物群落）通过形成生物膜来定居牙齿，假体，牙龈和舌头。已知一些细菌参与口腔疾病。例如，成人牙周炎中的龋齿和斑膜牙龈牙龈变形物中的链球菌和相关物种。另外，口腔细菌还与包括心内膜炎在内的其他类型的人类疾病有关。口腔细菌还通过与致病细菌的相互作用参与口腔疾病。因此，当前的牙齿疾病方法不仅是消除特定的病原菌，而且是促进可预防致病细菌群落定殖的细菌种群。但是，在正常状态和口腔疾病中口服菌群的发展在很大程度上是未知的。此外，尚未进行对宿主微生物感应受体控制微生物的研究，因此提出的研究将提供一个新的概念，以了解宿主如何控制有益和致病微生物的发展和稳态。预计这些研究的结果不仅可以为微生物感应受体和共生细菌之间的相互作用提供新颖的见解，还可以提供宿主受体和微生物层在牙周炎中的作用，这对于疾病的新颖和改善疗法至关重要。