A role for immune cell plasticity in commensal survival and escalation of inflammation

免疫细胞可塑性在共生生存和炎症升级中的作用

• 批准号: 9886553
• 负责人: Jason G Kay
• 金额: $ 39.11万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-06 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886553
• 关键词: Acute; Bacteria; Cell Death; Cells; Data; Development; Disease; Endocarditis; Environment; Exposure to; Goals; Growth; Immune; Immune system; Inflammasome; Inflammation; Inflammatory; Knowledge; Lesion; Leukocytes; Membrane; Microbe; Molecular; Oral; Oral cavity; Pathway interactions; Periodontal Diseases; Periodontitis; Phagocytes; Phagosomes; Phenotype; Play; Porphyromonas gingivalis; Prevention strategy; Production; Publishing; Reactive Oxygen Species; Research; Resistance; Rodent; Role; Streptococcus; Streptococcus gordonii; Testing; Tissues; Vesicle; commensal bacteria; commensal microbes; cytokine; dysbiosis; host-microbe interactions; immune activation; in vivo; in vivo Model; inflammatory modulation; macrophage; microbiome; microorganism; novel; oral commensal; oral streptococci; pathobiont; pathogen; prevent; receptor; recruit; response; tissue repair

Project Summary/Abstract Oral commensal microbes, including oral streptococci, are increasingly recognized as an essential component in the development of periodontal disease. Commensals contribute to the recruitment and growth of keystone disease-initiating microbes and are part of the dysbiotic disease-associated microbiome. Innate immune phagocytes, including macrophages, also play an essential role in the development of periodontal disease, and phagocytes themselves are phenotypically diverse. Interactions between phagocytes and keystone pathogens are well studied. However, relatively little is understood of the interactions between phagocytes and commensal streptococci. Also unknown is how an initial immune disruption by keystone pathogens can alter host immune interactions with oral streptococci that may enhance the latter’s contribution to disease. We have data highlighting a novel, yet counterintuitive, relationship between macrophages and S. gordonii: the bacterium is better able survive within, and promote enhanced cytokine release from, inflammatory macrophages. This new data, along with the knowledge that active periodontitis lesions have an increase in inflammatory macrophages leads us to our central hypothesis that upon initiation of inflammation, changes in macrophage-oral streptococci interactions allow the normally commensal bacterium to increase resistance to destruction and leads to enhanced cytokine production and inflammation. We will test our hypothesis by 1) assessing the molecular details of phagosomal escape and subsequent inflammatory promotion of S. gordonii within phagocytes, 2) determine the mechanisms of S. gordonii inflammatory modulation of macrophages initially activated by the keystone pathogen P. gingivalis and 3) begin to examine the in vivo mechanisms of increased S. gordonii survival within inflammatory macrophages. The overall aim of this research is to increase our understanding of the consequences of changes in host- commensal interactions upon initiation of inflammation. The rationale is that with an increased understanding of the conditions and molecular mechanisms by which commensals can act as pathobionts, we will achieve a first step in the long-term goal of developing new targets and strategies for the prevention and treatment of oral bacterial-associated inflammatory diseases.

项目总结/摘要 口腔微生物，包括口腔链球菌，越来越多地被认为是一种必需的微生物。 牙周病的危害有哪些？Commensals有助于招聘和成长， 关键的疾病引发微生物，并且是生态失调疾病相关微生物组的一部分。 先天免疫吞噬细胞，包括巨噬细胞，也在肿瘤的发生中起重要作用。 牙周病和吞噬细胞本身是表型多样的。吞噬细胞之间的相互作用 并且对关键病原体进行了充分的研究。然而，人们对它们之间的相互作用了解得相对较少。 吞噬细胞和链球菌。同样未知的是keystone最初的免疫破坏 病原体可以改变宿主与口腔链球菌的免疫相互作用， 疾病 我们有数据强调了巨噬细胞和S.戈登： 细菌能够更好地在炎性细胞内存活，并促进炎性细胞释放增强细胞因子 巨噬细胞这项新的数据，沿着的知识，即活动性牙周炎病变有增加， 炎症巨噬细胞导致我们的中心假设，即在炎症开始时， 巨噬细胞-口腔链球菌的相互作用使正常的口腔细菌增加了对 破坏并导致细胞因子产生和炎症增强。我们将通过以下方式检验我们的假设：1） 评估S.戈登链球菌 （2）确定S.巨噬细胞的戈登氏炎性调节 3）开始检查由关键病原体牙龈卟啉单胞菌激活的牙龈卟啉单胞菌的增加的体内机制， S.戈登氏菌在炎性巨噬细胞内存活。 这项研究的总体目标是增加我们对宿主变化后果的理解， 炎症开始时的神经相互作用。理由是，随着对 共生体可以充当致病生物的条件和分子机制，我们将首次实现 为预防和治疗口腔疾病制定新的目标和策略的长期目标的一步， 细菌相关的炎症性疾病。