T Cell Response to Listeria Monocytogenes Infection

T 细胞对单核细胞增生李斯特菌感染的反应

• 批准号: 7743006
• 负责人: Leo Lefrancois
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743006
• 关键词: Anatomy; Animal Model; Antigen-Presenting Cells; Attenuated Vaccines; Bacterial Infections; Bacterial Vaccines; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cells; Data; Dendritic Cells; Development; Gene Expression; Generations; Genetic; Genetic Programming; Goals; Heating; Imaging technology; Immune response; Immunity; Immunization; Infection; Life; Link; Listeria monocytogenes; Maps; Measures; Mediating; Memory; Molecular Profiling; Mus; Oral; Pattern; Play; Process; Production; Proteins; Publishing; Recombinants; Reporter; Role; Shapes; Structure; System; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Time; Transgenic Organisms; Vaccination; Vaccines; Virulent; Work; base; biodefense; cytokine; gene induction; genetic profiling; killings; mRNA Expression; mutant; novel; pathogen; public health relevance; research study; response; vaccination strategy; vaccine candidate; vaccinology

DESCRIPTION (provided by applicant): The factors essential to induction of a protective immune response to bacterial infections are incompletely understood. In the case of Listeria monocytogenes (LM) infection, a category B Priority Pathogen, CD8 T cells are important in effecting sterilizing immunity. LM interfaces at multiple levels with vaccinology as well as the Biodefense initiative due to the significant potential of LM as a vaccine candidate but also as an agent for intentional contamination and generation of highly virulent recombinant strains. Our work has begun to examine the parameters required for effective immunization with killed or mutant LM as potential vaccine vehicles. Specifically, immunization with heat killed LM (HKL) or irradiated LM (IRL) induced distinct patterns of T cell activation characterized by much more robust CD8 T cell memory induction following vaccination with IRL. However, IRL immunization did not induce the level of T cell activation and memory induction obtained with live LM infection. Thus, this is an excellent system for delineation of the mechanisms involved in promotion of distinct degrees of CD8 T cell activation generated by distinct forms of the same pathogen. Based on our preliminary data, the newly proposed studies focus on integrating the anatomy of effective CD8 T cell immune response initiation and memory T cell reactivation with the costimulatory and genetic programming necessary to drive a protective immune response. The hypothesis that responses induced by live infection versus immunization with attenuated vaccines share common essential components to generate protective memory will be tested in three aims: Specific Aim 1. To determine the role of costimulation and CD4 T cell help in priming and protective recall responses following LM infection or vaccination. Specific Aim 2. To determine the anatomical features of effective CD8 T cell vaccination and recall responses. Specific Aim 3. To define the genetic signature of responding CD8 T cells in response to effective vaccination. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the reasons why some vaccines are more effective than others. By studying different forms of a bacterial vaccine, our studies will help us devise more effective vaccination strategies.

描述（由申请人提供）：诱导针对细菌感染的保护性免疫反应所必需的因素尚不完全清楚。在 B 类优先病原体单核细胞增生李斯特菌 (LM) 感染的情况下，CD8 T 细胞在影响灭菌免疫方面发挥着重要作用。由于LM作为候选疫苗以及作为故意污染和产生高毒力重组菌株的媒介的巨大潜力，LM在多个层面上与疫苗学以及生物防御计划相结合。我们的工作已经开始研究以灭活或突变的LM作为潜在疫苗载体进行有效免疫所需的参数。具体来说，热灭活 LM (HKL) 或辐照 LM (IRL) 免疫诱导了不同的 T 细胞激活模式，其特征是 IRL 疫苗接种后 CD8 T 细胞记忆诱导更加强烈。然而，IRL 免疫并没有诱导活 LM 感染所获得的 T 细胞激活和记忆诱导水平。因此，这是一个很好的系统，用于描述促进同一病原体的不同形式产生的不同程度的 CD8 T 细胞激活的机制。根据我们的初步数据，新提出的研究重点是将有效 CD8 T 细胞免疫反应启动和记忆 T 细胞重新激活的解剖结构与驱动保护性免疫反应所需的共刺激和遗传编程相结合。活体感染诱导的反应与减毒疫苗免疫诱导的反应具有共同的产生保护性记忆的基本成分的假设将在三个目标中进行测试： 具体目标 1. 确定共刺激和 CD4 T 细胞的作用有助于在 LM 感染或疫苗接种后启动和保护性回忆反应。具体目标 2. 确定有效 CD8 T 细胞疫苗接种的解剖学特征和回忆反应。具体目标 3. 确定响应有效疫苗接种的 CD8 T 细胞的遗传特征。公共卫生相关性：该提案的目标是确定某些疫苗比其他疫苗更有效的原因。通过研究不同形式的细菌疫苗，我们的研究将帮助我们设计出更有效的疫苗接种策略。