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: 10308409
• 负责人: Jason G Kay
• 金额: $ 38.72万
• 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/10308409
• 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.

项目概要/摘要 口腔共生微生物，包括口腔链球菌，越来越被认为是一种重要的微生物。 牙周病发展的组成部分。共生有助于招募和成长 关键疾病引发微生物，是与失调疾病相关的微生物组的一部分。 先天免疫吞噬细胞，包括巨噬细胞，在免疫系统的发育中也发挥着重要作用。 牙周病和吞噬细胞本身的表型是多样的。吞噬细胞之间的相互作用 和关键病原体得到了充分研究。然而，人们对它们之间的相互作用知之甚少。 吞噬细胞和共生链球菌。同样未知的是 Keystone 最初的免疫破坏是如何发生的 病原体可以改变宿主与口腔链球菌的免疫相互作用，这可能会增强后者对 疾病。 我们的数据强调了巨噬细胞和戈登沙门氏菌之间一种新颖但违反直觉的关系： 该细菌能够更好地在炎症中生存，并促进炎症中细胞因子的释放 巨噬细胞。这一新数据以及活动性牙周炎病变增加的知识 炎症巨噬细胞引导我们得出中心假设，即炎症发生后，巨噬细胞的变化 巨噬细胞-口腔链球菌相互作用使通常共生的细菌增强对细菌的抵抗力 破坏并导致细胞因子产生增强和炎症。我们将通过 1) 来检验我们的假设 评估戈登沙门氏菌吞噬体逃逸和随后炎症促进的分子细节 在吞噬细胞内，2) 初步确定 S. gordonii 巨噬细胞炎症调节的机制 由关键病原体牙龈卟啉单胞菌激活，3）开始检查增加的体内机制 戈登沙门氏菌在炎症巨噬细胞内存活。 这项研究的总体目标是加深我们对宿主变化后果的理解。 炎症开始时的共生相互作用。其理由是，随着对 共生体可以充当致病生物的条件和分子机制，我们将实现第一个 step in the long-term goal of developing new targets and strategies for the prevention and treatment of oral 细菌相关的炎症性疾病。