Role of RANTES in Pneumococcal Immunopathogenesis

描述（由申请方提供）：由于易感个体无法产生适当的抗多糖抗体应答，以及在较小程度上产生表面蛋白抗体应答，以及抗生素耐药性增加，肺炎链球菌感染变得越来越难以控制。因此，非常需要新的预防性干预措施和对肺炎球菌免疫发病机制的理解。该建议源于并集中于我们最近的发现，即RANTES（调节激活，正常T细胞表达和分泌）显着，但差异，增强粘膜和全身免疫。我们目前的初步数据表明，RANTES mRNA粘膜表达升高的主要炎症/适应性识别反应肺炎球菌携带，这表明RANTES是必不可少的保护性粘膜免疫S。肺炎感染。RANTES、MIP-1 α和CCR 5多态性导致表达减少也与人类对其他粘膜病原体的易感性增加和进展有关。在这方面，我们的初步结果表明，RANTES阻断导致携带肺炎球菌的小鼠模型转变为致死性肺炎。pneumoniae菌株EF 3030。这些发现为支持RANTES对诱导保护性粘膜和系统适应性免疫抵抗链球菌的假说提供了理论基础。肺炎。 我们已经强调了使用肺炎球菌携带和肺炎的小鼠模型来检验这一假设的体内方法。目的研究正常小鼠、RANTES阻断小鼠和T细胞阻断小鼠对EF 3030的识别期免疫应答。目的2将表征适应性（激活/效应阶段）的粘膜和全身免疫反应的磷酸胆碱决定簇的C-多糖（PC）和肺炎球菌表面粘附素A（PsaA）在肺炎球菌疾病在对照Ab治疗或RANTES抑制小鼠。目的三将确定RANTES在保护免受由野生型、突变型表面蛋白（例如，psaA-）和粗糙型EF 3030菌株。这项研究将提供重要的和新的信息有关的细胞和分子机制，RANTES用于诱导对肺炎球菌的保护性免疫。

DESCRIPTION (provided by applicant): Streptococcus pneumoniae infections are becoming increasingly difficult to manage due to the inability of susceptible individuals to mount appropriate anti -polysaccharide and, to a lesser degree, -surface protein antibody responses as well as increasing antibiotic resistance. Hence, new prophylactic interventions and understanding of pneumococcal immunopathogenesis are greatly needed. This proposal stems from and focuses on our recent findings that RANTES (regulated on activation, normal T cell expressed and secreted) significantly, yet differentially, enhances mucosal and systemic immunity. We present preliminary data that RANTES mRNA mucosal expression is elevated during the primary inflammatory/adaptive recognition response to pneumococcal carriage, which suggests that RANTES is essential for protective mucosal immunity to S. pneumoniae infections. RANTES, MIP-1alpha, and CCR5 polymorphisms resulting in diminished expression are also associated with increased susceptibility to- and progression of- other mucosal pathogens in man. In this regard, our preliminary results show that RANTES blockade leads to the transition of pneumococcal carriage to lethal pneumonia in a mouse model of carriage, using S. pneumoniae strain EF3030. These findings provide the rationale to support the hypothesis that RANTES is essential for the induction of protective mucosal and systemic adaptive immunity against S. pneumoniae. We have emphasized in vivo approaches using mouse models of pneumococcal -carriage and -pneumonia to test this hypothesis. Aim One will assess the recognition phase host immune response to EF3030 challenge in normal, RANTES- or T cell- blocked mice. Aim Two will characterize the adaptive (activation/effector phase) mucosal and systemic immune responses to the phosphorylcholine determinant of C-polysaccharide (PC) and pneumococcal surface adhesin A (PsaA) during pneumococcal disease in control Ab-treated or RANTES-inhibited mice. Aim Three will ascertain the role of RANTES in protection against carriage and/or pneumonia induced by wild type, mutant surface protein (e.g., psaA-) and rough EF3030 strains. This study will provide important and new information regarding the cellular and molecular mechanisms that RANTES uses to induce protective immunity against pneumococci.