Inflammasome activation by a respiratory virus

呼吸道病毒激活炎症小体

• 批准号: 7641573
• 负责人: CHRISTOPHER M WIETHOFF
• 金额: $ 21.93万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641573
• 关键词: Adaptor Signaling Protein; Adenovirus Infections; Adenovirus Protein; Adenovirus Vector; Adenoviruses; Affect; Antiviral Agents; Attenuated; Capsid Proteins; Caspase-1; Cell Death; Cells; Cessation of life; Complex; Dependence; Development; Equilibrium; Future; Gene Transduction Agent; Generations; HIV; Half-Life; Hepatitis C; IRF3 gene; Immune response; Immune system; Immunity; Infection; Influenza; Interleukin-1; Interleukin-12; Interleukin-18; Interleukins; Invaded; Lead; Link; Mediating; Modeling; Molecular; Multiprotein Complexes; Mus; Mutation; NF-kappa B; Pathogenesis; Phagocytes; Play; Post-Transcriptional Regulation; Process; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Recruitment Activity; Relative (related person); Reporting; Role; Serotyping; Signal Transduction; Site; Tissues; Toll-like receptors; Tropism; Vaccines; Viral; Viral Pathogenesis; Viral Vector; Virus; Virus Diseases; base; cytokine; design; gene therapy; genetic vaccine; improved; macrophage; novel; pathogen; procaspase-1; protein degradation; public health relevance; receptor; respiratory; respiratory virus; response; vaccination strategy; vector

DESCRIPTION (provided by applicant): Proinflammatory responses to many viruses are important for clearance of the viral infection by the immune system. The importance of key proinflammatory molecules, IL-12 and IL-18, in mediating an immune response to adenovirus infection has been documented in mice. Release of these cytokines by macrophages at the site of viral infection recruits additional phagocytes and directs the quality and quantity of the adaptive immune response. Too much of these cytokines can, however, contribute to the pathogenesis of viral infection by enhancing the damage to infected tissues. The importance of the precise control of IL-12 and IL-18 release in response to various pathogens and danger signals is evidenced by the complex transcriptional and post- transcriptional control of IL-12 and IL-18 release from cells in response to infection. Ultimately, the secretion of IL-12 and IL-18 depends upon the activity of a multiprotein complex known as the inflammasome. This complex activates the interleukin-1 convertase, caspase-1, resulting in cleavage of proIL-12 and proIL-18 to secretion competent `mature' forms. Adenovirus was recently shown to activate the NALP3 inflammasome but the mechanism remains poorly defined. Given the important antiviral function of IL-12 and IL-18 in responding to adenovirus infections, we will examine the mechanisms of adenovirus mediated release of IL-12 from macrophages and examine the mechanisms of adenovirus induced macrophage cell death. We will determine the role of adenovirus capsid proteins in activating the inflammasome via NALP3 and the adaptor protein ASC. We will explore potential mechanisms used by adenoviruses with respiratory tropism to attenuate inflammasome activation. Finally, the dependence of adenovirus induced death of macrophages on specific inflammasome components and the contribution of this death process to the proinflammatory response will be elucidated. Results from these studies will provide novel information regarding molecular mechanisms for sensing viral infection which strongly influence the immune response to the virus. Given the importance of adenovirus vectors for gene therapy and genetic vaccination, results from these studies could aid in the design of improved gene therapy vectors which are no longer limited by the immune response to the vector. Alternatively, these studies may provide information which will result in the development of Ad-based genetic vaccines possessing more precise control of the immune response to achieve maximal protective immunity against pathogens such as HIV, hepatitis C or influenza. PUBLIC HEALTH RELEVANCE: A better description of the initiation of immune responses to viral infection will greatly aid in our understanding of viral pathogenesis and allow for the development of more effective antiviral treatments and vaccination strategies. Using the respiratory pathogen, adenovirus, as a model we will define the mechanisms involved in recognition of viral infection by the innate immune system. Additionally, since adenovirus is currently being explored as viral vector for genetic vaccines against HIV and influenza, a better understanding of how adenovirus is recognized by the immune system will allow us to more carefully tailor the immune response to adenovirus-based genetic vaccines.

描述（由申请人提供）：对许多病毒的促炎反应对于免疫系统清除病毒感染很重要。关键促炎分子IL-12和IL-18的重要性在介导对腺病毒感染的免疫反应中的重要性已在小鼠中记录。通过巨噬细胞在病毒感染部位释放这些细胞因子，募集了其他吞噬细胞，并指导适应性免疫反应的质量和数量。但是，这些细胞因子中的太多可以通过增强对感染组织的损害来导致病毒感染的发病机理。 IL-12和IL-18释放对各种病原体和危险信号的精确控制的重要性证明了IL-12和IL-18的复杂转录和转录后控制对感染的响应。最终，IL-12和IL-18的分泌取决于称为炎症体的多蛋白络合物的活性。该复合物激活白介素-1转化酶caspase-1，从而导致proil-12和proil-18裂解为分泌能力的“成熟”形式。最近显示腺病毒可激活Nalp3炎症体，但该机制的定义仍然很差。鉴于IL-12和IL-18在应对腺病毒感染中的重要抗病毒功能，我们将检查腺病毒介导的IL-12从巨噬细胞释放的机理，并检查腺病毒诱导的巨噬细胞死亡的机制。我们将确定腺病毒衣壳蛋白在通过NALP3和衔接蛋白ASC激活炎症体中的作用。我们将探讨腺病毒使用的潜在机制，呼吸道度疗法减轻炎症体激活。最后，将阐明腺病毒诱导的巨噬细胞死亡对特定炎症体成分的死亡以及该死亡过程对促炎反应的贡献。这些研究的结果将提供有关传感病毒感染的分子机制的新颖信息，这些信息强烈影响对病毒的免疫反应。鉴于腺病毒媒介对基因治疗和遗传疫苗接种的重要性，这些研究的结果可以有助于设计改进的基因治疗载体，而基因治疗载体不再受到对载体的免疫反应的限制。另外，这些研究可能会提供信息，从而导致基于AD的遗传疫苗具有对免疫反应的更精确控制，从而实现针对HIV，HIV，乙型肝炎或流感的病原体的最大保护性免疫。公共卫生相关性：更好地描述对病毒感染的免疫反应的启动将极大地帮助我们理解病毒发病机理，并允许发展更有效的抗病毒治疗和疫苗接种策略。使用呼吸道病原体腺病毒作为模型，我们将定义与先天免疫系统识别病毒感染有关的机制。此外，由于目前正在探索腺病毒作为针对HIV和HIV和流感的遗传疫苗的病毒载体，因此对免疫系统识别腺病毒的识别方式更好地理解了对基于腺病毒的遗传疫苗的免疫反应。