Microbial Disruption of Dendritic Cell Maturation and Function

几种人类病原体表达结构不同的A类脂蛋白，即内毒素的生物活性部分， 作为逃避先天免疫检测和确定慢性感染的一种策略。口腔粘膜病原体 牙龈卟啉单胞菌固有地表达低酰化的脂类A部分，并能改变 脂质A的磷酸化，导致TLR4信号的改变。除了局部免疫病理学，有意义的 临床和实验证据表明牙龈假单胞菌是慢性牙周炎发生的危险因素 全身性炎症性疾病，包括类风湿性关节炎、癌症和心血管疾病。 调节失调的T细胞反应被认为在这些炎症性疾病中发挥了作用。虽然这一角色 建立了逃避天然免疫信号的脂质A修饰，这如何影响获得性免疫 导致宿主免疫失调的反应还没有被探索。髓系树突状细胞 (DC)及其血液单核细胞前体在连接先天和适应性臂中发挥重要作用。 革兰氏阴性细菌感染时的免疫系统。这些细胞中TLR4的激活诱导了不同的 促进其动员到免疫T细胞区域以启动抗原特异性的成熟表型 豁免权。尽管关于牙龈假单胞菌在口腔中的致病机制的研究很丰富，但免疫学 牙龈假单胞菌介导的全身性炎症的机制尚不清楚。 在这项应用中，我们建议确定牙龈假单胞菌类脂A部分对DC反应和T细胞的影响 参与牙龈假单胞菌介导的全身免疫病理的激活。我们假设 牙龈假单胞菌表达的不同类脂A可驱动DC反应，导致不同的T细胞活化 促进牙龈假单胞菌介导的全身性炎症结果的途径。以下是目标 建议检验这一假说：目的1.明确牙龈假单胞菌脂类A种类和TLR4信号转导途径的作用 在DC应答和T细胞体外激活方面。目的2.明确牙龈假单胞菌类脂A对TLR4的作用。 口腔感染牙龈假单胞菌后依赖的DC和T细胞反应。目的3.明确P。 牙周炎不同类脂A及DC特异性TLR4信号在牙周炎致病中的作用 活体免疫病理学。 值得注意的是，几种表达免疫逃避类脂A的革兰氏阴性细菌与 自身免疫性疾病、动脉粥样硬化和癌症的风险。因此，这些研究具有广泛的影响，并将 对革兰氏阴性病原体改变全身适应性的机制提供了重要的见解 免疫反应导致的免疫病理学。 好了！

Several human pathogens express structurally divergent forms of lipid A, the biologically active moiety of LPS, as a strategy to evade innate immune detection and establish chronic infection. The oral mucosal pathogen Porphyromonas gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. In addition to local immunopathology, significant clinical and experimental evidence implicate P. gingivalis as risk factor for the development of chronic systemic inflammatory diseases including rheumatoid arthritis, cancer, and cardiovascular disease. Dysregulated T cell responses are believed to play a role in these inflammatory disorders. While the role of lipid A modifications in evasion of innate immune signaling is established, how this influences adaptive immune responses that contribute to dysregulation of host immunity has not been explored. Myeloid dendritic cells (DCs) and their blood monocyte precursors play an important role in bridging the innate and adaptive arms of the immune system during Gram-negative bacterial infection. TLR4 activation in these cells induces a distinct maturation phenotype that promotes their mobilization to immune T cell areas for initiation of antigen-specific immunity. Despite the wealth of studies on P. gingivalis pathogenesis in the oral cavity, the immunological mechanisms underlying P. gingivalis mediated systemic inflammation are not well defined. We propose in this application to define the impact of P. gingivalis lipid A moieties on DC responses and T cell activation that contribute to P. gingivalis mediated systemic immunopathology. We hypothesize that the different lipid A species expressed by P. gingivalis drive DC responses leading to distinct T cell activation pathways that contribute to P. gingivalis-mediated systemic inflammatory outcomes. The following Aims are proposed to test this hypothesis: Aim 1. To define the role of P. gingivalis lipid A species and TLR4 signaling in DC responses and T cell activation in vitro. Aim 2.To define the role of P. gingivalis lipid A species on TLR4- dependent DC and T cell responses following P. gingivalis oral infection. Aim 3. To define the role of P. gingivalis distinct lipid A species and DC-specific TLR4 signaling in the development of P. gingivalis induced immunopathology in vivo. Strikingly, several Gram-negative bacteria that express immune-evasive lipid A are associated with increased risk of autoimmune disease, atherosclerosis, and cancer. Thus, these studies have broad implications and will provide important insights into the mechanisms by which Gram-negative pathogens alter systemic adaptive immune responses resulting immunopathology. !