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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：
10237941
负责人：
Caroline A Genco
金额：
$ 61.27万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237941
关键词：
Affect Agonist Anaerobic Bacteria Antigen-Presenting Cells Antigens Apolipoprotein E Area Atherosclerosis Autoimmune Diseases Bacteria Biological 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 Phenotype Phosphoric Monoester Hydrolases Phosphorylation Play Porphyromonas gingivalis Rheumatoid Arthritis Risk Risk Factors Role Signal Transduction Site Structure 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 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结构不同的脂质A，脂质A是脂多糖的生物活性部分，