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Microbial Disruption of Dendritic Cell Maturation and Function

树突状细胞成熟和功能的微生物破坏

基本信息

批准号：
10468732
负责人：
Caroline A Genco
金额：
$ 58.61万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468732
关键词：
Affect Agonist Anaerobic Bacteria Antigen-Presenting Cells Antigens Apolipoprotein E Area Atherosclerosis Autoimmune Diseases Bacteria Bone Diseases Cardiovascular Diseases Cell Maturation Cell physiology Cells Chronic Clinical Dendritic Cells Detection Development Disease Equilibrium Exhibits Gram-Negative Bacteria Gram-Negative Bacterial Infections Human Immune Immune Evasion Immune response Immune signaling Immune system Immunity Immunologic Receptors Immunologics In Vitro Inflammation Inflammatory Lipid A Malignant Neoplasms Measures Mediating Modeling Modification Mus Myelogenous Natural Immunity Nature Oral Oral cavity Oral mucous membrane structure Outcome Ovalbumin Pathogenesis Pathway interactions Periodontal Diseases Persons Phenotype Phosphoric Monoester Hydrolases Phosphorylation Play Porphyromonas gingivalis Rheumatoid Arthritis Risk Risk Factors Role Signal Transduction Site T cell differentiation T cell response T-Cell Activation T-Cell Activation Pathway T-Lymphocyte TLR2 gene TLR4 gene Testing Transgenic Organisms United States adaptive immune response adaptive immunity antagonist arm base chronic infection human pathogen immunopathology in vivo insight microbial monocyte mutant non-alcoholic fatty liver disease oral infection pathogen pathogenic microbe receptor response systemic inflammatory response vascular inflammation

项目摘要

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. !

几种人类病原体表达脂质 A 的结构不同形式，脂质 A 是 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本质上表达未酰化的脂质 A 部分，并且可以修饰脂质 A 磷酸化，导致 TLR4 信号传导改变。除了局部免疫病理学外，显着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炎症性疾病，包括类风湿性关节炎、癌症和心血管疾病。据信，T 细胞反应失调在这些炎症性疾病中发挥着作用。虽然角色脂质 A 修饰可逃避先天免疫信号传导，这如何影响适应性免疫导致宿主免疫失调的反应尚未被探索。骨髓树突状细胞 (DC) 及其血液单核细胞前体在连接先天性和适应性臂方面发挥着重要作用。革兰氏阴性细菌感染期间的免疫系统。这些细胞中的 TLR4 激活诱导了独特的促进其动员至免疫 T 细胞区域以启动抗原特异性的成熟表型免疫。尽管对口腔牙龈卟啉单胞菌发病机制进行了大量研究，但免疫学牙龈卟啉单胞菌介导的全身炎症的机制尚未明确。我们建议在此申请中定义牙龈卟啉单胞菌脂质 A 部分对 DC 反应和 T 细胞的影响有助于牙龈卟啉单胞菌介导的全身免疫病理学的激活。我们假设牙龈卟啉单胞菌表达的不同脂质 A 驱动 DC 反应，导致不同的 T 细胞激活有助于牙龈卟啉单胞菌介导的全身炎症结果的途径。以下目标是建议检验这一假设：目标 1. 定义牙龈卟啉单胞菌脂质 A 物种和 TLR4 信号传导的作用体外 DC 反应和 T 细胞激活。目标 2. 确定牙龈卟啉单胞菌脂质 A 物种对 TLR4- 的作用牙龈卟啉单胞菌口腔感染后依赖的 DC 和 T 细胞反应。目标 3. 定义 P 的角色。牙龈卟啉单胞菌独特的脂质A物种和DC特异性TLR4信号传导在牙龈卟啉单胞菌诱导的发育中体内免疫病理学。引人注目的是，几种表达免疫逃避脂质 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为革兰氏阴性病原体改变系统适应性的机制提供重要见解免疫反应导致免疫病理学。！

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microbial Lipid A Remodeling Controls Cross-Presentation Efficiency and CD8 T Cell Priming by Modulating Dendritic Cell Function.

微生物脂质 A 重塑通过调节树突状细胞功能来控制交叉呈递效率和 CD8 T 细胞启动。

DOI：
10.1128/iai.00335-20
发表时间：
2021
期刊：
Infection and immunity
影响因子：
3.1
作者：
Papadopoulos,George;Berland,Robert;Sunkavalli,Ashwini;Coats,StephenR;Darveau,RichardP;Genco,CarolineA
通讯作者：
Genco,CarolineA