Repression of inflammasome by Francisella tularensis

土拉弗朗西斯菌对炎症小体的抑制

• 批准号: 8574070
• 负责人: Meenakshi Malik
• 金额: $ 46.5万
• 依托单位: ALBANY COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-16 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574070
• 关键词: AIM2 gene; Address; Affect; Attenuated Vaccines; Biological Assay; Caspase-1; Categories; Cell Death; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Collaborations; Complex; Cysteine Protease; Cytolysis; Cytosol; DNA; Defense Mechanisms; Development; Disease; Ensure; Francisella; Francisella tularensis; Gene Components; Generations; Genetic Screening; Genetic Transcription; Goals; Health Sciences; Immune; Immune response; Immune system; Immunotherapeutic agent; In Vitro; Infection; Inflammatory; Interferon Type I; Interferons; Interleukin-1; Interleukin-18; Knowledge; Libraries; Ligands; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Natural Immunity; New York; Outcome Study; Pathogenesis; Pharmacy facility; Production; Receptor Signaling; Repression; Research; Research Project Grants; Resolution; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Toll-like receptors; Tularemia; Vaccines; Virulence; Virulent; base; college; combat; cytokine; experience; human disease; in vivo; macrophage; medical schools; microbial; mutant; pathogen; prevent; programs; prophylactic; public health relevance; receptor; research facility; response; sensor

DESCRIPTION (provided by applicant): Francisella tularensis (Ft) is a gram-negative intracellular pathogen that causes a fatal disease known as tularemia. Based on its high virulence, use in bioweapon programs in the past, and potential to be used in bioterror attacks, the Centers for Disease Control (CDC) have classified Ft as a Category A select agent. The extreme virulence of Ft is due to its ability to subvert host's innate immune response. In support of this notion, our preliminary studies demonstrate that the virulent strain Ft SchuS4 and Live Vaccine Strain (LVS), a derivative of F. holarctica exert suppressive effects on innate immune signaling cascades resulting in very low levels of pro-inflammatory cytokines associated with significant delay in the programmed death of the infected cells. However, the mechanisms and the Francisella factors mediating these effects are ill defined. Two major classes of innate immune sensors, Toll-like receptors (TLRs) and cytosolic Nod-like receptors (NLRs) are activated in response to specific microbial components. Activation of these sensors leads to induction of pro- inflammatory cytokines, recruitment of innate immune cells to the sites of infection, generation of an adaptive immune response and resolution of infection. Recognition of pathogens by cytosolic NLRs activates assembly of a multi-molecular complex termed as inflammasome. The inflammasome complex activates cysteine protease caspase1 which in-turn activates pro-forms of pro-inflammatory cytokines IL-1¿ and IL-18 to their mature active forms. Inflammasome assembly and caspase-1 activation also induces a rapid form of pro- inflammatory cell death, termed pyroptosis. Our preliminary studies demonstrate that F. tularensis is capable of suppressing both TLR and NLR-mediated responses and pyroptotic cell death. This proposal is aimed at investigating the mechanism by which virulent strains of Ft suppress NLR-dependent responses. Our hypothesis is that "active repression of the inflammasome is essentially required for intracellular survival of Ft". We propose that by repressing or delaying this protective host's innate immune response, Ft is able to create a replicative niche in the cytosol leading to uncontrolled proliferation within the host macrophages. This hypothesis will be tested via Specific aim 1 which will establish the key sites of repression of inflammasome by Ft LVS and SchuS4 while in Specific aim 2, we will identify the mechanisms of Ft mediated repression of inflammasome. Ft serves as a unique model to understand the intricate mechanisms of inflammasome mediated responses. The outcome from these studies will identify mechanism(s) employed by Ft to repress the inflammasome, a critical host innate immune defense mechanism. These studies will advance our knowledge of tularemia pathogenesis and will bring us closer to achieving the ultimate goal of identifying the targets for development of effective therapeutics and prophylactics. This proposal is a step ahead in understanding the immunopathogenesis of tularemia.

描述（由申请人提供）：土拉菌Francisella tularensis （Ft）是一种革兰氏阴性的细胞内病原体，可引起一种称为土拉菌病的致命疾病。基于其高毒性，过去在生物武器计划中的使用，以及用于生物恐怖袭击的潜力，疾病控制中心（CDC）已将其列为a类精选剂。Ft的极端毒力是由于它能够破坏宿主的先天免疫反应。为了支持这一观点，我们的初步研究表明，毒力菌株Ft SchuS4和活疫苗菌株（LVS） （F. holarctica的衍生物）对先天免疫信号级联具有抑制作用，导致极低水平的促炎细胞因子与感染细胞的程序性死亡显著延迟相关。然而，介导这些作用的机制和Francisella因子尚未明确。两类主要的先天免疫传感器，toll样受体（TLRs）和细胞质nod样受体（NLRs）被激活以响应特定的微生物成分。这些传感器的激活导致促炎细胞因子的诱导，先天免疫细胞募集到感染部位，产生适应性免疫反应和感染的解决。细胞质nlr对病原体的识别激活了称为炎性体的多分子复合物的组装。炎性小体复合体激活半胱氨酸蛋白酶caspase1，进而激活促炎细胞因子IL-1和IL-18的前形式，使其达到成熟的活性形式。炎性小体的组装和caspase-1的激活也诱导了一种快速形式的促炎性细胞死亡，称为焦亡。我们的初步研究表明，土拉菌能够抑制TLR和nlr介导的反应和热噬细胞死亡。本研究旨在探讨Ft毒株抑制nlr依赖性反应的机制。我们的假设是“炎性小体的主动抑制是Ft细胞内存活所必需的”。我们认为，通过抑制或延迟这种保护性宿主的先天免疫反应，Ft能够在细胞质中创造一个复制生态位，导致宿主巨噬细胞内不受控制的增殖。