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如何通过单个微生物产物激活不同的先天免疫反应途径：细菌脂多糖（LPS）。尽管TLR4被广泛认可以控制对LP的转录响应，但存在TLR4独立的响应。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的非典型炎症激活。这些不同的LPS响应之间的关系在很大程度上是未知的，但是正如我们将描述的那样，至少某些独立于TLR4独立的响应控制了对LPS的经典定义的TLR4依赖性响应。了解微生物产物如何激活不同的信号转导途径可能允许设计可以针对一部分途径的药物或疫苗。我们的建议建立在我们最近的发现上，即LPS通过不需要功能性TLR4信号传导（TIR）域或其任何相关衔接蛋白的过程来诱导TLR4的内吞作用。相反，TLR4是通过LPS结合蛋白CD14激活的内吞作用途径的货物。尽管TLR4并未引导其自身的内吞作用，但对于TLR4诱导内体的TRIF依赖性信号转导至关重要。该发现提供了一个示例，说明了如何相互依存的TLR4依赖性和非依赖性响应。在此赠款应用中，我们建议1）确定CD14是否激活了通用信号通路，以引起多种细胞类型特异性的先天免疫反应，2）确定是否存在常见或不同的蛋白质复合物，以调节LPS诱导的LPS诱导信号途径的多样化，以及3）识别直接对LPS响应的细胞群体，这些细胞受到致病性细菌感染模型的直接对LPS的反应。总的来说，这项工作将为您提供重要的见解 对LP的各种细胞反应相互联系。