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

项目摘要/摘要 口腔共生微生物，包括口腔链球菌，越来越被认为是必不可少的 在牙周病的发生发展中起着重要作用。合同制有助于招聘和发展 Keystone是引发疾病的微生物，是与疾病相关的非生物微生物群的一部分。 包括巨噬细胞在内的先天免疫吞噬细胞在糖尿病的发生发展中也起着重要作用。 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 而Keystone病原体的研究也很深入。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最初的免疫中断是如何 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。 我们的数据突显了巨噬细胞和戈登葡萄球菌之间一种新的、但违反直觉的关系： 细菌能更好地在炎症中存活，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有增加的知识 炎性巨噬细胞将我们引向我们的中心假设，即在炎症开始时， 巨噬细胞-口腔链球菌的相互作用使正常共生细菌增加了对 破坏并导致细胞因子的产生增强和炎症。我们将通过1)来检验我们的假设 评估戈登葡萄球菌吞噬小体逃逸和随后的炎症促进的分子细节 在吞噬细胞内，2)初步确定戈登葡萄球菌对巨噬细胞炎症调节的机制 被牙龈假单胞菌激活和3)开始检测体内增加的机制 戈登氏杆菌在炎性巨噬细胞内存活。 这项研究的总体目的是增加我们对宿主变化的后果的了解。 炎症开始时的共生相互作用。其基本原理是，随着对 共生体作为致病因子的条件和分子机制，我们将实现第一个 为口腔疾病的预防和治疗制定新的目标和战略的长期目标 细菌相关的炎症性疾病。

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.