Initiation and regulation of antibacterial innate immunity

抗菌先天免疫的启动和调节

• 批准号: 8891586
• 负责人: JONATHAN C KAGAN
• 金额: $ 45.58万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891586
• 关键词: Adaptor Signaling Protein; Address; Animal Model; Anti-Bacterial Agents; Applications Grants; Bacterial Infections; Bacterial Typing; Biological Assay; CD14 gene; Caspase; Cells; Cytosol; Data; Dendritic Cells; Detection; Dimerization; Distal; Drug Design; Endocytosis; Endocytosis Pathway; Endosomes; Event; Goals; Health; Immune response; Immunity; Infection; Laboratories; Life; Lipopolysaccharides; Mediating; Microbe; Motion; Natural Immunity; Pathway interactions; Population; Process; Regulation; Research Proposals; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; TLR4 gene; Tissues; Transcriptional Regulation; Type III Secretion System Pathway; Vaccines; Virulence Factors; Work; Yersinia; activating transcription factor; base; cell type; genetic regulatory protein; immune activation; in vivo; insight; lipopolysaccharide-binding protein; macrophage; microbial; new technology; pathogenic bacteria; prevent; protein complex; receptor; response; tool; transcription factor

DESCRIPTION (provided by applicant): The goal of this proposal is to explain how diverse innate immune response pathways can be activated by a single microbial product: bacterial lipopolysaccharide (LPS). While TLR4 is widely recognized to control transcriptional responses to LPS, TLR4-independent responses exist. Examples of such responses include endocytosis, activation of the transcription factor NFAT, and activation of non-canonical inflammasomes by caspase-11. The relationship between these diverse LPS responses is largely unknown, but as we will describe, at least some TLR4-independent responses control the classically-defined TLR4-dependent responses to LPS. Understanding how microbial products activate distinct signal transduction pathways may permit the design of drugs or vaccines that can target a subset of pathways therapeutically. Our proposal is founded on our recent discovery that LPS-induces the endocytosis of TLR4 by a process that does not require a functional TLR4 signaling (TIR) domain, or any of its associated adaptor proteins. Rather TLR4 is cargo for an endocytosis pathway that is activated by the LPS-binding protein CD14. While TLR4 does not direct its own endocytosis, this process is essential for TLR4 to induce TRIF-dependent signal transduction from endosomes. This discovery provides an example of how TLR4-dependent and -independent responses to LPS can be interdependent. In this grant application, we propose to 1) determine if a common signaling pathway is activated by CD14 to elicit diverse cell type-specific innate immune responses, 2) determine if common or distinct protein complexes exist that regulate diverse LPS inducible signaling pathways, and 3) identify the cell populations that directly respond to LPS produced by pathogenic bacterial infections in animal models of infection. Collectively, this work will provide important insight into the means by which diverse cellular responses to LPS are interconnected.

描述（由申请人提供）：该提案的目的是解释单一微生物产物：细菌脂多糖（LPS）如何激活多种先天免疫反应途径。虽然 TLR4 被广泛认为可以控制 LPS 的转录反应，但存在不依赖于 TLR4 的反应。此类反应的例子包括内吞作用、转录因子 NFAT 的激活以及 caspase-11 对非经典炎症小体的激活。这些不同的 LPS 反应之间的关系在很大程度上是未知的，但正如我们将描述的，至少一些 TLR4 独立反应控制着经典定义的 TLR4 依赖性 LPS 反应。了解微生物产物如何激活不同的信号转导途径可能有助于设计能够针对部分途径进行治疗的药物或疫苗。我们的提议是基于我们最近的发现，即 LPS 通过不需要功能性 TLR4 信号传导 (TIR) 结构域或其任何相关接头蛋白的过程诱导 TLR4 的内吞作用。相反，TLR4 是由 LPS 结合蛋白 CD14 激活的内吞途径的货物。虽然 TLR4 不指导其自身的内吞作用，但该过程对于 TLR4 诱导内体的 TRIF 依赖性信号转导至关重要。这一发现提供了一个例子，说明 TLR4 依赖性和非 TLR4 对 LPS 的反应如何相互依赖。在本次拨款申请中，我们建议：1) 确定 CD14 是否激活共同的信号通路以引发不同细胞类型特异性的先天免疫反应，2) 确定是否存在调节不同 LPS 诱导信号通路的共同或独特的蛋白质复合物，以及 3) 确定在感染动物模型中对致病性细菌感染产生的 LPS 产生直接反应的细胞群。总的来说，这项工作将为我们提供重要的见解 对脂多糖的不同细胞反应是相互关联的。