Mechanisms of Immunity to Pneumococcal Colonization

肺炎球菌定植的免疫机制

• 批准号: 7266115
• 负责人: RICHARD MALLEY
• 金额: $ 42.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266115
• 关键词: 2 year old; Active Immunization; Adoptive Transfer; Agonist; Antibodies; Antigens; Bacteria; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cessation of life; Child; Clinical Trials; Conflict (Psychology); Confocal Microscopy; Conjugate Vaccines; Data; Dendritic Cells; Development; Disease; Encapsulated; Epidemiologic Studies; Evaluation; Goals; Grant; Human; Immune response; Immunity; Immunization; Immunization Programs; Immunologic Techniques; Infant; Inflammatory; Injection of therapeutic agent; Interferon Type II; Interleukin-17; Invasive; Knowledge; Laboratories; Lymphoid Tissue; Mediating; Modeling; Mus; Personal Satisfaction; Pilum; Play; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Polysaccharides; Proteins; Purpose; Refrigeration; Research Personnel; Resistance; Resistance development; Risk; Role; Sepsis; Serotyping; Streptococcus pneumoniae; T-Cell Development; T-Lymphocyte; Testing; Thinking; Time; Toll-like receptors; Work; World Health Organization; acquired immunity; base; capsule; cytokine; extracellular; human study; killings; neutrophil; novel; novel vaccines; pathogen; prevent; programs; receptor; research study; resistance mechanism; response; success

DESCRIPTION (provided by applicant): The overall theme of this grant is to understand mechanisms of acquired immunity to colonization by the encapsulated, extracellular bacterium Streptococcus pneumonias (pneumococcus), the cause of over 800,000 deaths from sepsis and pneumonia annually. Historically, antibody to the capsular polysaccharides has traditionally been viewed as the primary mechanism of immunity. In preliminary experiments, we found however that colonization with pneumococci could be prevented in the absence of antibody and that intranasal immunization by killed pneumococci protected antibody-deficient but not T-cell deficient mice, or mice that were congenitally deficient in CD4+ T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of CD8+ T cells were fully protected. Adoptive transfer of CD4+ cells from immunized mice protected RAG-deficient mice from subsequent pneumococcal colonization. IFN-gamma deficient mice were protected by WCV; however, IL-17A receptor-deficient mice were not. Intranasal immunization with a combination of three pneumococcal proteins conferred antibody- independent immunity to pneumococcal colonization. Thus, our data suggest that immunity to pneumococcal colonization can be induced in the absence of antibody and requires the presence of acquired, antigen-specific IL-17A-producing CD4+ T cells at the time of challenge. The purpose of this proposal is to test the hypothesis that, under the initial influence of innate immune responses, these specific IL-17A T cell-mediated responses play a critical role in acquired resistance to pneumococcal colonization. The overall goals of this project are to study the mechanisms whereby cellular immune responses protect against pneumococcal colonization and/or disease and determine whether engagement of toll-like receptors (TLRs) determines the development of these T cell responses. Experimental approaches will include T cell adoptive transfer experiments, polarization of Th responses, immunization of cytokine- and TLR-deficient mice, and use of defined pneumococcal components as immunogens and TLR agonists. The results of our experiments will define a previously-unrecognized mechanism of protection against extracellular encapsulated bacteria and help in the development of novel vaccines against pneumococcus.

描述（由申请人提供）：这项资助的总体主题是了解对有荚膜的细胞外细菌肺炎链球菌（肺炎球菌）定植的获得性免疫机制，每年导致超过 800,000 人死于败血症和肺炎。从历史上看，荚膜多糖抗体一直被视为免疫的主要机制。然而，在初步实验中，我们发现，在没有抗体的情况下，可以阻止肺炎球菌的定植，并且杀死的肺炎球菌的鼻内免疫可以保护抗体缺陷型小鼠，但不能保护 T 细胞缺陷型小鼠，或者先天性缺乏 CD4+ T 细胞或在攻击时这些细胞已耗尽的小鼠。相比之下，先天性缺乏或耗尽 CD8+ T 细胞的小鼠受到了充分的保护。来自免疫小鼠的 CD4+ 细胞的过继转移可保护 RAG 缺陷小鼠免受随后的肺炎球菌定植。 IFN-γ缺陷小鼠受到WCV的保护；然而，IL-17A 受体缺陷的小鼠则不然。使用三种肺炎球菌蛋白的组合进行鼻内免疫可赋予对肺炎球菌定植的抗体独立免疫力。因此，我们的数据表明，在没有抗体的情况下可以诱导对肺炎球菌定植的免疫，并且需要在攻击时存在获得性的、产生抗原特异性IL-17A的CD4+T细胞。该提案的目的是检验以下假设：在先天免疫反应的最初影响下，这些特定的 IL-17A T 细胞介导的反应在获得性肺炎球菌定植抵抗中发挥着关键作用。该项目的总体目标是研究细胞免疫反应防止肺炎球菌定植和/或疾病的机制，并确定 Toll 样受体 (TLR) 的参与是否决定这些 T 细胞反应的发展。实验方法将包括T细胞过继转移实验、Th反应的极化、细胞因子和TLR缺陷小鼠的免疫以及使用确定的肺炎球菌成分作为免疫原和TLR激动剂。我们的实验结果将定义一种以前未被认识的针对细胞外封装细菌的保护机制，并有助于开发针对肺炎球菌的新型疫苗。