Innate and acquired immune responses to novel pneumococcal T cell antigens

对新型肺炎球菌 T 细胞抗原的先天和获得性免疫反应

• 批准号: 8165370
• 负责人: KRISTIN LEIGH MOFFITT
• 金额: $ 13.35万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165370
• 关键词: ATP-Binding Cassette Transporters; Accounting; Advanced Development; Agonist; Animals; Antibodies; Antigens; Boston; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Clinical; Communicable Diseases; Communities; Complex; Data; Disease; Evaluation; Foundations; Generations; Goals; Health Priorities; Herd Immunity; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Receptors; Immunology; Infection; Interleukin-17; Laboratory Research; Lipids; Lipoprotein Binding; Lipoproteins; Mediating; Mentors; Mentorship; Methodology; Microbiology; Molecular; Molecular Profiling; Mus; Nasopharynx; Natural Immunity; Pathogenesis; Pediatric Hospitals; Play; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Polysaccharides; Principal Investigator; Protein Subunits; Proteins; Proteomics; Receptor Activation; Relative (related person); Research; Research Personnel; Research Project Grants; Resistance; Resources; Role; Sepsis; Serotyping; Site-Directed Mutagenesis; Specialist; Streptococcus pneumoniae; Subunit Vaccines; System; Systemic infection; T cell response; T-Lymphocyte; TLR2 gene; Testing; Time; Toll-Like Receptor 2; Toll-like receptors; Vaccines; Virulence; Work; acquired immunity; base; career; cost; cytokine; experience; extracellular; global health; immunogenic; immunogenicity; insight; macrophage; medical schools; mortality; mouse model; mucosal vaccine; mutant; novel; pathogen; prevent; research study; response; transmission process; vaccine development

DESCRIPTION (provided by applicant): This proposal describes a five year mentored research project with the goal of characterizing the innate and acquired immune responses to two novel pneumococcal T cell antigens. The principal investigator's clinical background as a pediatric infectious diseases specialist and scientific background in pneumococcal T cell antigen discovery serve as the foundation on which these research endeavors will build. Successful completion of this project will provide the principal investigator with the experience in molecular microbiology, expression analysis and innate immunology methodologies necessary for transition to independence as an investigator in bacterial pathogenesis and evaluation of host pathogen interactions. This work will occur within the research laboratories of the Division of Infectious Diseases at Children's Hospital Boston with abundant scientific resources available within the division and the surrounding community of Harvard Medical School. For scientific and career guidance, this work will progress with the mentorship of Dr. Richard Malley, an expert in the field of pneumococcal immunity and vaccine development, and the co-mentorship of Dr. Douglas Golenbock, an expert in innate immune mechanisms. There has recently been a paradigm shift in the understanding of mechanisms of acquired immunity to numerous mucosal pathogens. Work of the Malley lab and others has shown that IL-17A-secreting CD4+ T cells (TH17 cells) mediate resistance to colonization with Streptococcus pneumoniae in an antibody- independent manner. From proteomic screens completed with Dr. Malley and collaborators, the principal investigator has identified several novel antigens based on their recognition by TH17 cells of mice immunologically protected from pneumococcal colonization. Several of these proteins protect animals from pneumococcal colonization when used as mucosal vaccines. Of these proteins, two are lipoproteins that appear to activate the innate immune Toll-like receptor (TLR) 2. Based on the hypothesis that the innate immune stimulatory potential of these proteins is contributing to the protection they confer, the proposed work will further characterize these proteins with a focus on the interaction between the innate and acquired immune responses they elicit. This work proposes to determine 1) whether these proteins are TLR2 agonists, 2) the role of these proteins in pneumococcal pathogenesis and 3) the role of TLR2 in the generation of protective immune responses to these proteins. This study aims to elucidate the mechanism of immunity elicited by two proteins that may be strong candidates for a protein subunit pneumococcal vaccine and may enhance the understanding of pneumococcal interaction with the host immune system. Infections with Streptococcus pneumoniae account for an estimated 11% of mortality in young children worldwide making an affordable, serotype-independent pneumococcal vaccine a global health priority. A vaccine that prevents colonization would have a double-edged advantage, as it would reduce the major manifestations of pneumococcal disease and contribute to a reduction in transmission rates thereby enhancing the herd immunity conferred by immunization. Further characterization of candidate proteins and elucidation of the mechanism of immunity they elicit are critical to advance the development of a protein subunit vaccine that prevents colonization.

描述（由申请人提供）：该提案描述了一个为期五年的指导研究项目，其目的是表征对两种新型肺炎球菌T细胞抗原的先天和获得的免疫反应。主要研究者作为小儿传染病专家和肺炎球菌T细胞抗原发现的科学背景的临床背景是这些研究努力将建立的基础。该项目的成功完成将为主要研究者提供分子微生物学，表达分析和先天免疫学方法的经验，即过渡到独立性作为细菌发病机理和宿主病原体相互作用评估的研究者。这项工作将发生在波士顿儿童医院传染病分区的研究实验室中，并在哈佛医学院的部门和周围社区内提供了丰富的科学资源。为了获得科学和职业指导，这项工作将在肺炎球菌免疫和疫苗开发领域的专家Richard Malley博士以及Douglas Golenbock博士的合作（先天性免疫机制专家）的教会中进行。最近，对获得众多粘膜病原体的免疫机制的理解发生了范式转变。 Malley Lab等人的工作表明，分泌CD4+ T细胞（Th17细胞）的IL-17A的作品可介导肺炎链球菌以抗体独立的方式介导对定殖的抗性。从与Malley博士和合作者一起完成的蛋白质组学筛查中，首席研究者根据其识别了几种新型抗原，这些抗原的Th17细胞的识别是对受肺炎球菌菌落的免疫学保护的小鼠的识别。这些蛋白质中的几种用作粘膜疫苗，可以保护动物免受肺炎球菌定殖。在这些蛋白质中，两种是脂蛋白，它们似乎激活了先天免疫电话（TLR）2。基于以下假设：这些蛋白质的先天免疫刺激潜力是为它们提供的保护做出的贡献，拟议的工作将进一步将这些蛋白质的焦点侧重于与天生的免疫反应之间的相互作用来表征它们，从而进一步表征它们。这项工作建议确定1）这些蛋白是否是TLR2激动剂，2）这些蛋白质在肺炎球菌发病机理中的作用，以及3）TLR2在对这些蛋白质的保护性免疫反应中的作用。这项研究旨在阐明两种蛋白质引起的免疫机制，这些蛋白可能是蛋白质亚基肺炎球菌疫苗的强大候选者，并可能增强对肺炎球菌与宿主免疫系统相互作用的理解。肺炎链球菌感染估计占全球幼儿死亡率的11％，这使得负担得起的，与血清型独立的肺炎球菌疫苗成为全球健康的重点。一种防止定殖的疫苗将具有双刃优势，因为它将减少肺炎球菌疾病的主要表现，并有助于降低传播速率，从而增强免疫免疫赋予的群体免疫力。候选蛋白的进一步表征和阐明其引起的免疫机制对于推动阻止定殖的蛋白质亚基疫苗的发展至关重要。