Mechanisms of Immunity to Pneumococcal Colonization

肺炎球菌定植的免疫机制

基本信息

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
项目类别：
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

项目摘要

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）：该赠款的总体主题是了解通过封装的，细胞外细菌肺炎链球菌（肺炎球菌）获得的免疫机制，这是每年超过800,000人死亡的原因。从历史上看，传统上将囊囊多糖的抗体视为免疫的主要机制。在初步实验中，我们发现，在没有抗体的情况下，可以防止用肺炎球菌定殖，并且被杀死的肺炎球体鼻内免疫免疫可保护肺炎的缺陷，而不是T细胞缺陷的小鼠，或者在CD4+ T细胞或在这些细胞中遭受挑战的小鼠或在这些细胞中造成了任何挑战。相反，在CD8+ T细胞中先天缺乏或耗尽的小鼠得到了充分保护。从免疫小鼠中转移CD4+细胞，保护抹布缺陷的小鼠免受随后的肺炎球菌定殖。 IFN-gamma缺乏小鼠受WCV保护；但是，IL-17A受体缺陷小鼠尚未。鼻内免疫与三种肺炎球菌蛋白的组合赋予抗体独立于肺炎球菌定殖的免疫。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，并且需要在挑战时存在获得的，抗原特异性IL-17A产生的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对肺炎球菌定植的抗性中起着至关重要的作用。该项目的总体目标是研究细胞免疫反应可预防肺炎球菌定殖和/或疾病的机制，并确定收费类受体（TLR）的参与是否确定这些T细胞反应的发展。实验方法将包括T细胞产物转移实验，TH反应的极化，细胞因子和TLR缺陷小鼠的免疫，以及使用定义的肺炎球菌成分作为免疫原子和TLR激动剂。我们的实验结果将定义一种以前未认可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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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