Listeria-induced cytosolic response and host immunity

描述(由申请人提供)：这项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间隔中的微生物，引发病原体特异性免疫反应，并产生保护性免疫。单核细胞增多性李斯特菌是一种胞内细菌，它在巨噬细胞中激活两组不同的转录反应：依赖于MyD88的反应在细胞表面和空泡识别期间启动，以及依赖于IRF3的反应在胞浆进入时启动。这种细菌将被用作模式微生物，以确定依赖IRF3的胞浆反应在急性感染和长期免疫中发挥什么作用。单核细胞增多性乳杆菌突变株改变了多药耐药转运蛋白的表达，从而诱导了不同程度的胞浆基因表达，将被用来确定感染过程中胞液反应的影响。第一个特定的目的是在缺乏TLR介导的反应的情况下，研究急性单核细胞增多性李斯特菌感染过程中胞浆反应的贡献。第二个特定目标的目的是阐明胞浆反应是否与树突状细胞成熟和T细胞启动有关。最后，第三个具体目标将解决胞浆反应是否有助于T细胞介导的保护性免疫反应的产生。揭示IRF3介导的胞浆反应对单核细胞增多性李斯特菌的作用可能揭示一种新的先天免疫机制，这一机制对于产生保护性免疫非常重要，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激发免疫反应，建立对特定病原微生物的长期保护性免疫。这项提案中概述的研究将检查感染单核细胞增多性李斯特菌的早期炎症反应如何导致免疫记忆的产生，以防止再次感染。这项工作将有助于理解炎症是如何产生长期记忆的，并可能揭示开发安全有效疫苗的方法的新见解。

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.