Listeria-induced cytosolic response and host immunity

李斯特菌诱导的细胞质反应和宿主免疫

• 批准号: 7943967
• 负责人: Kristina Ann Archer
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943967
• 关键词: Acute; Address; Bacteria; Cell Maturation; Cell surface; Cytosol; Dendritic Cells; Gene Expression; Generations; Goals; IRF3 gene; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Infection; Infection Control; Inflammation; Inflammatory Response; Knowledge; Life; Listeria; Listeria monocytogenes; Mediating; Methods; Microbe; Modeling; Multi-Drug Resistance; Mus; Pathway interactions; Play; Research; Role; Signal Transduction; T memory cell; T-Lymphocyte; Vaccine Design; Vaccines; Vacuole; Work; adaptive immunity; insight; long term memory; macrophage; microorganism; mutant; pathogen; response; vaccine development

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand how the host recognizes and discriminates between microbes that live in distinct cellular compartments, elicits a pathogen-specific immunological response, and generates protective immunity. Listeria monocytogenes is an intracellular bacterium that activates two distinct sets of transcriptional responses in macrophages: a MyD88-dependent response initiated during cell surface and vacuolar recognition and an IRF3-dependent response initiated during cytosolic entry. This bacterium will be used as a model microorganism to determine what role the IRF3- dependent cytosolic response plays during acute infection and long-term immunity. L. monocytogenes mutants that have altered expression of multidrug resistance transporters and consequently induce varying magnitudes of cytosolic gene expression will be exploited to determine the effect of the cytosolic response during infection. The first specific aim will examine the contribution ofthe cytosolic response during acute L. monocytogenes infection in the absence of the TLR-mediated responses. The goal of the second specific aim is to elucidate whether the cytosolic response is involved in dendritic cell maturation and T cell priming. Finally, the third specific aim will address whether the cytosolic response contributes to the generation of T- cell mediated protective immune responses. Uncovering the role of the IRF3-mediated cytosolic response to L. monocytogenes could reveal a new innate immune mechanism important for the generation of protective immunity, knowledge that would be instrumental for vaccine development. The major challenge of vaccine design is how to elicit an immune response that establishes long-term protective immunity against a specific pathogenic microorganism. The research outlined in this proposal will examine how the early inflammatory response to infection with the bacterium Listeria monocytogenes leads to the generation of immunological memory that protects against reinfection. This work will contribute to the understanding of how inflammation generates long-term memory and may reveal new insights on methods to develop safe and effective vaccines.

描述（由申请人提供）：本提案的长期目标是了解宿主如何识别和区分生活在不同细胞区室中的微生物，激发病原体特异性免疫反应，并产生保护性免疫。单核细胞增生李斯特菌是一种细胞内细菌，激活巨噬细胞中两组不同的转录反应：在细胞表面和空泡识别期间启动的MyD88依赖性反应和在胞质进入期间启动的IRF3依赖性反应。该细菌将被用作模型微生物，以确定IRF3依赖性胞质应答在急性感染和长期免疫中起什么作用。L.将利用改变了多药耐药转运蛋白表达并因此诱导不同程度的胞质基因表达的单核细胞增多症突变体来确定感染期间胞质应答的作用。第一个具体的目标是研究急性L.在TLR介导的反应的情况下，单核细胞增多症感染。第二个具体目标的目标是阐明胞质应答是否参与树突状细胞成熟和T细胞引发。最后，第三个具体目标将解决胞质应答是否有助于T细胞介导的保护性免疫应答的产生。揭示IRF3介导的胞质对L.单核细胞增多症可能揭示了一种新的先天免疫机制，这种机制对保护性免疫的产生很重要，这一知识将有助于疫苗的开发。疫苗设计的主要挑战是如何引发免疫应答，建立针对特定病原微生物的长期保护性免疫。该提案中概述的研究将研究对单核细胞增生李斯特菌感染的早期炎症反应如何导致免疫记忆的产生，以防止再感染。这项工作将有助于理解炎症如何产生长期记忆，并可能揭示开发安全有效疫苗的方法的新见解。