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:
  • 金额:
    $ 61.27万
  • 依托单位:
  • 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

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,

项目成果

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Caroline A Genco其他文献

Caroline A Genco的其他文献

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{{ truncateString('Caroline A Genco', 18)}}的其他基金

Porphyromonas gingivalis and Pancreatic Carcinogenesis in Mouse Models
小鼠模型中牙龈卟啉单胞菌与胰腺癌发生
  • 批准号:
    9519194
  • 财政年份:
    2018
  • 资助金额:
    $ 61.27万
  • 项目类别:
Microbial Disruption of Dendritic Cell Maturation and Function
树突状细胞成熟和功能的微生物破坏
  • 批准号:
    10468732
  • 财政年份:
    2018
  • 资助金额:
    $ 61.27万
  • 项目类别:
Microbial Disruption of Dendritic Cell Maturation and Function
树突状细胞成熟和功能的微生物破坏
  • 批准号:
    9790936
  • 财政年份:
    2018
  • 资助金额:
    $ 61.27万
  • 项目类别:
The Gonococcal Fur Regulon Link to Pathogenesis
淋球菌毛皮调节子与发病机制的联系
  • 批准号:
    9751634
  • 财政年份:
    2017
  • 资助金额:
    $ 61.27万
  • 项目类别:
Global Transcriptome Analysis of Mucosal Gonoccal Infection
粘膜淋菌感染的全局转录组分析
  • 批准号:
    9333190
  • 财政年份:
    2016
  • 资助金额:
    $ 61.27万
  • 项目类别:
TLR4 evasion, bacterial persistence and chronic inflammation
TLR4 逃避、细菌持续存在和慢性炎症
  • 批准号:
    8926492
  • 财政年份:
    2014
  • 资助金额:
    $ 61.27万
  • 项目类别:
TLR4 evasion, bacterial persistence and chronic inflammation
TLR4 逃避、细菌持续存在和慢性炎症
  • 批准号:
    9117800
  • 财政年份:
    2014
  • 资助金额:
    $ 61.27万
  • 项目类别:
Global transcriptome analysis of mucosal gonococcal infection
粘膜淋球菌感染的全局转录组分析
  • 批准号:
    9101453
  • 财政年份:
    2014
  • 资助金额:
    $ 61.27万
  • 项目类别:
Global transcriptome analysis of mucosal gonococcal infection
粘膜淋球菌感染的全局转录组分析
  • 批准号:
    8889364
  • 财政年份:
    2014
  • 资助金额:
    $ 61.27万
  • 项目类别:
P. gingivalis Mediated Evasion Strategies
牙龈卟啉单胞菌介导的逃避策略
  • 批准号:
    8532592
  • 财政年份:
    2013
  • 资助金额:
    $ 61.27万
  • 项目类别:

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