Role of RANTES in Pneumococcal Immunopathogenesis

描述（由申请人提供）：肺炎链球菌感染变得越来越难以控制，因为易感个体无法产生适当的抗多糖，在较小程度上，表面蛋白抗体反应以及抗生素耐药性的增加。因此，迫切需要新的预防干预措施和对肺炎球菌免疫发病机制的了解。这一建议源于并关注于我们最近的研究结果，即RANTES（调节激活，正常T细胞的表达和分泌）显著但差异地增强了粘膜和全身免疫。我们提供的初步数据表明，在对肺炎球菌携带的原发性炎症/适应性识别反应中，RANTES mRNA粘膜表达升高，这表明RANTES对肺炎链球菌感染的保护性粘膜免疫至关重要。RANTES、mip -1 α和CCR5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，在使用肺炎链球菌菌株EF3030的小鼠载体模型中，RANTES阻断导致肺炎球菌载体向致死性肺炎转变。这些发现为RANTES对诱导保护性粘膜和系统性肺炎链球菌适应性免疫至关重要的假设提供了理论依据。我们强调了使用肺炎球菌携带和肺炎小鼠模型的体内方法来验证这一假设。目的一将评估正常、RANTES或T细胞阻断小鼠对EF3030攻击的识别期宿主免疫反应。目的二将在对照抗体处理或rantes抑制小鼠中表征肺炎球菌疾病期间对c -多糖（PC）和肺炎球菌表面粘附素A （PsaA）的磷酸化胆碱决定因素的适应性（激活/效应期）粘膜和全身免疫反应。目的三将确定RANTES在防止野生型、突变表面蛋白（如psaA-）和粗糙的EF3030菌株引起的携带和/或肺炎中的作用。这项研究将为RANTES用于诱导对肺炎球菌的保护性免疫的细胞和分子机制提供重要的新信息。

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.