Synergistic extra and intracellular recognition of F. tularensis

土拉弗朗西斯胞外和胞内的协同识别

• 批准号: 7589310
• 负责人: Meenakshi Malik
• 金额: $ 23.55万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-22 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589310
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Bacteria; Binding; Caspase; Caspase-1; Categories; Cell Death; Cell surface; Cells; Cellular biology; Cytoplasm; Dendritic Cells; Development; Disease; Environment; Event; Exhibits; Family; Francisella; Francisella tularensis; Goals; Histopathology; Host Defense; Immune; Immune response; Immunity; Immunotherapeutic agent; In Vitro; Infection; Inflammatory; Inflammatory Response; Interferon Inducers; Interferon Type I; Interferons; Interleukin-18; Interleukin-6; Invaded; Laboratories; Ligands; Lipoproteins; Mediating; Molecular; Mus; Mutation; Natural Immunity; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Play; Positioning Attribute; Predisposition; Process; Production; Proteins; Receptor Signaling; Reporting; Role; Signal Pathway; Signal Transduction; Site; Surface; TLR2 gene; Testing; Toll-like receptors; Tularemia; Vaccines; Virulent; biosafety level 3 facility; biothreat; cell type; combat; cytokine; disease phenotype; expectation; experience; extracellular; in vivo; innovation; macrophage; member; microbial; mortality; pathogen; protein complex; public health relevance; receptor; research study; respiratory; response; sensor; tool

DESCRIPTION (provided by applicant): Surface-expressed Toll-like receptors (TLRs) and a newly described class of cytosolic pattern recognition receptors (PRRs), members of the Nod-like receptor (NLR) family, play a major role in innate host defense against the intracellular pathogen Francisella tularensis, a category A biothreat agent. Recently it was shown that F.tularensis triggers TLR2 signaling in immune cells and that mutation of this PRR is associated with greater susceptibility to infection. Similarly, signaling through apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), an NLR adaptor molecule, and subsequent caspase-1 activation were shown to be essential for eliciting protective immunity to F. tularensis infection. One intriguing question which remains unanswered is the precise relationship between the TLR and NLR signaling pathways and whether activation of NLRs in response to F. tularensis occurs downstream of TLRs or proceeds independent of TLR signaling. Furthermore, the specific component(s) of F. tularensis that triggers the downstream signaling events and the receptor(s) of the NLR pathways are not known. This proposal seeks to address these issues by testing the hypothesis that integration of signals transduced via the TLR2 and NLR pathway is required for the optimal development of innate immune responses to F. tularensis infection via the following Specific Aims: 1) Identify the F. tularensis SchuS4 component(s) activating the NLR pathway and evaluate the role of select NLRs in mediating the pro-inflammatory responses to F. tularensis. 2) Establish the key sites of integration between the TLR2 and NLR signaling pathways in response to F. tularensis SchuS4. This proposal will study the cell biology of signal integration between key components of innate immunity and how these processes at the cellular level contribute to the host's ability to resist microbial challenge. Defining the molecular mechanism(s) of innate immunity will be an essential first step towards development of immunotherapeutic, as well as effective vaccine strategies to combat a variety of intracellular bacterial pathogens. This proposal is innovative because it provides a comprehensive approach to explore the relatively unknown signal integration between extra- and intracellular innate immune mechanisms following F. tularensis SchuS4 infection in our CDC-approved ABSL3/BSL3 facility. This study will identify the F. tularensis component(s) and the receptor(s) responsible for triggering the cytosolic machinery and elucidate the molecular mechanisms by which extra- and intracellular signals are integrated to elicit an optimal innate immune response. PUBLIC HEALTH RELEVANCE: This proposal aims to investigate the immunopathologic mechanisms underlying tularemia, a zoonotic disease caused by Francisella tularensis, a Category A biothreat agent. The studies will focus on exploring the cell biology of signal integration between key components of innate immunity and how these processes at the cellular level contribute to the host's ability to resist microbial challenge. Defining the molecular mechanism(s) of innate immunity will be an essential first step towards development of immunotherapeutic, as well as effective vaccine strategies to combat this fatal disease.

描述（由申请人提供）：表面表达的 Toll 样受体 (TLR) 和新描述的一类胞质模式识别受体 (PRR)，属于 Nod 样受体 (NLR) 家族的成员，在宿主针对细胞内病原体土拉弗朗西斯菌（一种 A 类生物威胁因子）的先天防御中发挥着重要作用。最近的研究表明，土拉弗拉菌会触发免疫细胞中的 TLR2 信号传导，并且这种 PRR 的突变与更高的感染易感性相关。同样，通过包含 caspase 募集结构域 (ASC)、NLR 接头分子的凋亡相关斑点样蛋白发出的信号以及随后的 caspase-1 激活对于引发针对土拉弗朗西斯虫感染的保护性免疫至关重要。一个尚未得到解答的有趣问题是 TLR 和 NLR 信号通路之间的精确关系，以及 NLR 响应土拉弗拉菌的激活是发生在 TLR 下游还是独立于 TLR 信号传导进行。此外，土拉弗朗西斯触发下游信号事件的特定成分和 NLR 途径的受体尚不清楚。本提案旨在通过测试以下假设来解决这些问题：通过 TLR2 和 NLR 途径转导的信号整合对于针对土拉弗朗西斯感染的先天免疫反应的最佳发展是必需的，具体目标如下： 1) 识别激活 NLR 途径的土拉弗朗西斯 SchuS4 成分，并评估选定的 NLR 在介导促炎反应中的作用。 F. tularensis。 2) 建立 TLR2 和 NLR 信号通路之间响应 F. tularensis SchuS4 的关键整合位点。该提案将研究先天免疫关键成分之间信号整合的细胞生物学，以及细胞水平上的这些过程如何有助于宿主抵抗微生物挑战的能力。定义先天免疫的分子机制将是开发免疫治疗以及对抗各种细胞内细菌病原体的有效疫苗策略的重要第一步。该提案具有创新性，因为它提供了一种全面的方法来探索在我们 CDC 批准的 ABSL3/BSL3 设施中土拉弗朗西斯 SchuS4 感染后细胞外和细胞内先天免疫机制之间相对未知的信号整合。这项研究将鉴定负责触发胞质机制的土拉弗朗西斯菌成分和受体，并阐明整合细胞外和细胞内信号以引发最佳先天免疫反应的分子机制。公共健康相关性：本提案旨在研究兔热病的免疫病理学机制，兔热病是一种由 A 类生物威胁因子土拉弗朗西斯菌引起的人畜共患疾病。这些研究将重点探索先天免疫关键成分之间信号整合的细胞生物学，以及细胞水平上的这些过程如何有助于宿主抵抗微生物挑战的能力。定义先天免疫的分子机制将是开发免疫治疗以及对抗这种致命疾病的有效疫苗策略的重要第一步。