Microbial Disruption of Dendritic Cell Maturation and Function

几种人类病原体表达结构上不同形式的脂质A，LPS的生物活性部分， 作为逃避先天免疫检测和建立慢性感染的策略。口腔粘膜病原体 牙龈卟啉单胞菌固有地表达酰化不足的脂质A部分，并且可以修饰脂质A部分。 脂质A的磷酸化，导致改变的TLR 4信号传导。除了局部免疫病理学， 临床和实验证据表明牙龈卟啉单胞菌是慢性牙周炎发展的危险因素。 全身性炎性疾病，包括类风湿性关节炎、癌症和心血管疾病。 失调的T细胞应答被认为在这些炎性疾病中起作用。虽然作用 脂质A修饰在逃避先天免疫信号传导中的作用已经确立，这是如何影响适应性免疫的 导致宿主免疫失调的应答尚未被探索。髓样树突细胞 (DCs)和它们的血液单核细胞前体在连接先天性和适应性的手臂中起着重要的作用， 革兰氏阴性菌感染时的免疫系统。TLR 4在这些细胞中的激活诱导了一种独特的 成熟表型，促进其动员到免疫T细胞区域，用于启动抗原特异性免疫应答。 免疫力尽管关于牙龈卟啉单胞菌在口腔中的发病机制的研究很多，但免疫学上， 牙龈卟啉单胞菌介导的全身性炎症的潜在机制尚未明确。 在本申请中，我们提出定义牙龈卟啉单胞菌脂质A部分对DC应答和T细胞免疫应答的影响。 激活，有助于牙龈卟啉单胞菌介导的全身免疫病理学。我们假设 牙龈卟啉单胞菌表达的不同脂质A种类驱动DC应答，导致不同的T细胞活化 促进牙龈卟啉单胞菌介导的全身炎症结果的途径。以下目标是 为了验证这个假设，我们提出了一个假设：目标1。确定牙龈卟啉单胞菌脂质A种类和TLR 4信号传导的作用 在体外DC应答和T细胞活化中。目的2.明确牙龈卟啉单胞菌类脂A对TLR 4 - 1的作用。 牙龈卟啉单胞菌口腔感染后依赖DC和T细胞的反应。目标3。明确P的作用。 牙龈卟啉单胞菌不同的脂质A种类和DC特异性TLR 4信号转导在牙龈卟啉单胞菌的发展中诱导 体内免疫病理学 引人注目的是，几种表达免疫逃避性脂质A的革兰氏阴性细菌与增加的 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意义，并将 提供了重要的洞察机制，革兰氏阴性病原体改变系统适应性 免疫反应导致免疫病理学。 !

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. !