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: 7749571
• 负责人: Meenakshi Malik
• 金额: $ 19.43万
• 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 2010-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749571
• 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（由申请方提供）：表面表达的Toll样受体（TLR）和一种新描述的胞质模式识别受体（PRR），即Nod样受体（NLR）家族成员，在宿主对细胞内病原体土拉弗朗西斯菌（一种A类生物威胁剂）的先天防御中发挥主要作用。最近显示，土拉热杆菌触发免疫细胞中的TLR 2信号传导，并且该PRR的突变与对感染的更大易感性相关。类似地，通过包含半胱天冬酶募集结构域（ASC）、NLR接头分子的凋亡相关斑点样蛋白的信号传导以及随后的半胱天冬酶-1活化被证明是引发对F的保护性免疫所必需的。土拉菌感染一个有趣的问题是TLR和NLR信号通路之间的确切关系，以及是否激活NLR响应F。 土拉热发生在TLR下游或独立于TLR信号传导进行。此外，F. 触发下游信号传导事件的土拉热和NLR途径的受体尚不清楚。该提案试图通过测试以下假设来解决这些问题：通过TLR 2和NLR途径转导的信号的整合是对F的先天免疫应答的最佳发展所必需的。土拉热菌感染的特异性目的：1）鉴定土拉热菌; tularensis SchuS 4组分激活NLR通路，并评估选择的NLR在介导对F.土拉热。2)建立TLR 2和NLR信号通路整合的关键位点，以响应F。土拉菌4.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，以及这些过程在细胞水平上如何有助于宿主抵抗微生物挑战的能力。确定先天免疫的分子机制将是发展免疫学的重要第一步，也是对抗各种细胞内细菌病原体的有效疫苗策略。这一建议是创新的，因为它提供了一个全面的方法来探索相对未知的信号整合之间的额外和细胞内的先天免疫机制，以下F。 在我们CDC批准的ABSL 3/BSL 3设施中发现土拉菌SchuS 4感染。本研究将确定F.图拉热菌组分和负责触发胞质机制的受体，并阐明了整合细胞外和细胞内信号以引发最佳先天免疫应答的分子机制。公共卫生相关性：该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。这些研究将侧重于探索先天免疫关键成分之间信号整合的细胞生物学，以及这些过程在细胞水平上如何有助于宿主抵抗微生物挑战的能力。确定先天免疫的分子机制将是发展免疫学的重要第一步，也是对抗这种致命疾病的有效疫苗策略。