Mechanisms of Immunity to Pneumococcal Colonization

肺炎球菌定植的免疫机制

• 批准号: 8018651
• 负责人: RICHARD MALLEY
• 金额: $ 40.62万
• 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/8018651
• 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; Histological Techniques; Human; Immune response; Immunity; Immunization; Immunization Programs; Immunologic Techniques; Infant; Inflammatory; Injection of therapeutic agent; Interferon Type II; Interleukin-17; Laboratories; Lymphoid Tissue; Mediating; Modeling; Mus; Passive Immunization; Pilum; Play; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Polysaccharides; Proteins; Refrigeration; Research Personnel; Resistance; Resistance development; Role; Sepsis; Serotyping; Streptococcus pneumoniae; T cell response; T-Lymphocyte; Testing; Time; Toll-like receptors; Work; acquired immunity; base; capsule; cytokine; extracellular; high risk; human data; 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）：该资助的总体主题是了解获得性免疫对包囊化的细胞外细菌肺炎链球菌（肺炎球菌）定植的机制，肺炎链球菌每年导致80多万人死于败血症和肺炎。历史上，抗荚膜多糖的抗体传统上被认为是免疫的主要机制。然而，在初步实验中，我们发现在没有抗体的情况下可以防止肺炎球菌的定植，并且通过杀死的肺炎球菌的鼻内免疫保护抗体缺陷但不保护T细胞缺陷小鼠，或先天性CD 4 + T细胞缺陷或在攻击时这些细胞耗尽的小鼠。相比之下，先天缺乏或耗尽CD 8 + T细胞的小鼠得到了完全保护。免疫小鼠的CD 4+细胞的连续转移保护了RAG缺陷小鼠免受随后的肺炎球菌定植。IFN-γ缺陷型小鼠受WCV保护;然而，IL-17 A受体缺陷型小鼠不受保护。三种肺炎球菌蛋白的组合鼻内免疫赋予了对肺炎球菌定殖的抗体非依赖性免疫。因此，我们的数据表明，免疫肺炎球菌定植可以在抗体的情况下诱导，并需要在挑战时获得的抗原特异性IL-17 A产生的CD 4 + T细胞的存在。该提议的目的是检验以下假设：在先天免疫应答的初始影响下，这些特异性IL-17 A T细胞介导的应答在对肺炎球菌定植的获得性抗性中起关键作用。该项目的总体目标是研究细胞免疫应答保护免受肺炎球菌定植和/或疾病的机制，并确定Toll样受体（TLR）的参与是否决定了这些T细胞应答的发展。实验方法将包括T细胞过继转移实验、Th应答极化、细胞因子和TLR缺陷小鼠的免疫接种，以及使用定义的肺炎球菌组分作为免疫原和TLR激动剂。我们的实验结果将确定一个以前未被认识的机制，保护对细胞外包裹的细菌，并有助于开发新的疫苗对肺炎球菌。

项目成果

Broad antibody and T cell reactivity induced by a pneumococcal whole-cell vaccine.

肺炎球菌全细胞疫苗诱导广泛的抗体和 T 细胞反应性。

• DOI: 10.1016/j.vaccine.2012.01.034
• 发表时间: 2012
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Moffitt,KristinL;Yadav,Puja;Weinberger,DanielM;Anderson,PorterW;Malley,Richard
• 通讯作者: Malley,Richard

T(H)17-based vaccine design for prevention of Streptococcus pneumoniae colonization.

• DOI: 10.1016/j.chom.2011.01.007
• 发表时间: 2011-02-17
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Moffitt KL;Gierahn TM;Lu YJ;Gouveia P;Alderson M;Flechtner JB;Higgins DE;Malley R
• 通讯作者: Malley R

GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis.

• DOI: 10.1016/j.vaccine.2010.09.031
• 发表时间: 2010-11-03
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Lu, Ying-Jie;Leite, Luciana;Goncalves, Viviane Maimoni;Dias, Waldely de Oliveira;Liberman, Celia;Fratelli, Fernando;Alderson, Mark;Tate, Andrea;Maisonneuve, Jean-Francois;Robertson, George;Graca, Rita;Sayeed, Sabina;Thompson, Claudette M.;Anderson, Porter;Malley, Richard
• 通讯作者: Malley, Richard

Streptococcus pneumoniae carriage in the Gaza strip.

• DOI: 10.1371/journal.pone.0035061
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Regev-Yochay G;Abullaish I;Malley R;Shainberg B;Varon M;Roytman Y;Ziv A;Goral A;Elhamdany A;Rahav G;Raz M;Palestinian-Israeli Collaborative Research Study Group
• 通讯作者: Palestinian-Israeli Collaborative Research Study Group