Variable Gene Defects and Pneumococcal Susceptibility

描述（由申请人提供）：这是一项竞争性续期申请，旨在继续研究肺炎链球菌（肺炎球菌）的抗体（Ab）免疫。该建议的重点是宿主免疫状态与抗体对肺炎球菌性肺炎的保护之间的关系。肺炎球菌性肺炎是美国和全球社区获得性肺炎的主要原因。自2000年以来，由于群体免疫，肺炎球菌结合疫苗的使用导致儿童和成人侵袭性肺炎球菌疾病的急剧下降。尽管如此，非疫苗血清型（ST）也有所增加，包括ST3，这是本次应用的重点。老年人和免疫功能低下及合并症患者仍然是肺炎球菌病的最高风险人群。非疫苗性STs的出现，肺炎球菌荚膜多糖（PPS）疫苗是否能预防成人肺炎的不确定性，以及美国免疫功能低下和老年人数量的增加，都强调需要更好地了解PPS疫苗的疗效和失败机制，特别是在免疫功能低下的患者中。我们小组在之前的研究期间的一些新发现与这个问题有关：1)在体外不具有抗噬细胞作用的单克隆抗体（mab）能够保护小鼠免受肺炎球菌的肺部攻击；2)非调理噬细胞单克隆抗体对小鼠的作用与炎症反应的调节有关；3) pps蛋白偶联物和免疫血清需要CD8 T细胞来保护小鼠免受ST3肺炎球菌的致死性肺攻击。该建议的假设是，疫苗对肺炎球菌肺炎的有效性需要抗体控制细菌负担并调节免疫反应，这取决于抗体与细胞免疫成分之间的合作。具体目的是：1)确定CD8 T细胞对小鼠ST3肺炎的保护作用；2)确定T细胞和Ab型对小鼠抗ST3抗体保护的贡献；3)探讨PMNs和巨噬细胞对小鼠ST3型肺炎抗体的保护作用。我们提出的研究将促进对疫苗功效的理解，揭示抗体免疫抗肺炎的新机制，并与肺炎球菌肺炎的预防和治疗直接相关，特别是在免疫功能低下的患者中。公共卫生相关性：使用儿童肺炎链球菌结合疫苗（肺炎球菌疫苗）降低了成人和儿童侵袭性肺炎球菌疾病的发病率。这是一个重大的进步。然而，疫苗中出现的肺炎球菌菌株，特别是免疫功能低下的患者，以及目前成人肺炎球菌疫苗是否能预防肺炎的不确定性，强调了改进疫苗的必要性，特别是免疫功能低下的患者。肺炎球菌疫苗通过激发抗体（Ab）来预防疾病。这项应用的目的是揭示宿主免疫状态对抗体抗肺炎的重要性，这与肺炎球菌性肺炎的预防和治疗直接相关，特别是在免疫功能低下的患者中。拟议的研究将促进我们对肺炎球菌疫苗如何起作用的理解。

DESCRIPTION (provided by applicant): This is a competitive renewal application to continue studies of antibody (Ab) immunity to Streptococcus pneumoniae (pneumococcus). The focus of the proposal is on the relationship between the immune status of the host and Ab protection against pneumococcal pneumonia. Pneumococcal pneumonia is the leading cause of community acquired pneumonia in the U.S. and globally. Since 2000, use of the pneumococcal conjugate vaccine has led to a dramatic decline in invasive pneumococcal disease in children and in adults due to herd immunity. Nonetheless, there has been an increase in non-vaccine serotypes (ST), including ST3, which is the focus of this application. The elderly and patients with immunocompromised states and co-morbid conditions continue to be at the highest risk for pneumococcal disease. The emergence of non-vaccine STs, uncertainty as to whether pneumococcal capsular polysaccharide (PPS) vaccines prevent pneumonia in adults, and the increased number of immunocompromised and elderly people in the U.S., underscore the need for a better understanding of mechanisms of PPS vaccine efficacy and failure, particularly in immunocompromised patients. Several novel findings from our group during the previous finding period are relevant to this question: 1) monoclonal antibodies (MAbs) that were not opsonophagocytic in vitro were able to protect mice against pulmonary challenge with pneumococcus; 2) the efficacy of non-opsonophagocytic MAbs in mice was associated with modulation of the inflammatory response; and 3) CD8 T cells were required for a PPS-protein conjugate and immune serum to protect mice against lethal pulmonary challenge with ST3 pneumococcus. The hypothesis of this proposal is that vaccine efficacy against pneumococcal pneumonia requires Abs that control of the bacterial burden and modulate the immune response and that this depends on collaboration between Ab and components of cellular immunity. The specific aims are: 1) To determine the role that CD8 T cells play in protection against ST3 pneumonia in mice; 2) To determine the contribution of T cells and Ab type to Ab protection against ST3 in mice; 3) To determine the role of PMNs and macrophages in Ab protection against ST3 pneumonia in mice. The studies we propose will advance understanding of vaccine efficacy and reveal novel mechanisms of Ab immunity against pneumonia and have direct relevance to prevention and treatment of pneumococcal pneumonia, particularly in immunocompromised patients. PUBLIC HEALTH RELEVANCE: Use of a pediatric conjugate vaccine (pneumococcal vaccine) for Streptococcus pneumoniae has resulted in a reduction in the incidence of invasive pneumococcal disease in adults and children. This is a major advance. However, the emergence of pneumococcal strains that are not in the vaccine, particularly in immunocompromised patients, and uncertainty as to whether the current pneumococcal vaccine for adults prevents pneumonia, underscore the need for improved vaccines, particularly for immunocompromised patients. Pneumococcal vaccines work by eliciting antibodies (Ab) that prevent disease. The aims of this application, which propose to reveal the importance of the immune status of the host to Ab protection against pneumonia, have direct relevance to prevention and treatment of pneumococcal pneumonia, particularly in immunocompromised patients. The proposed studies will advance our understanding of how pneumococcal vaccine works.