Role of RANTES in Pneumococcal Immunopathogenesis

RANTES 在肺炎球菌免疫发病机制中的作用

• 批准号: 7237187
• 负责人: James W Lillard
• 金额: $ 24.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237187
• 关键词: 6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-one; Address; Antibiotic Resistance; Antibodies; Antibody Formation; Antigens; Bacterial Adhesins; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cellular Immunity; Computer software; Control Groups; Data; Development; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Genetic Polymorphism; Hepatitis B e Antigens; Image; Immune response; Immunity; Immunization; Immunoglobulin A; Individual; Infection; Infectious Agent; Inflammatory; Interleukin-10; Intervention; Kinetics; Leukocytes; Life; Ligands; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Mediating; Medical Surveillance; Membrane Proteins; Messenger RNA; Molecular; Mucosal Immunity; Mus; Nose; Numbers; Organ; Pathogenesis; Phase; Phosphorylcholine; Play; Pneumococcal Infections; Pneumonia; Polysaccharides; Predisposition; Production; Research; Role; Series; Serum; Small Inducible Cytokine A3; Spleen; Streptococcus pneumoniae; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Virulence Factors; capsule; cytokine; day; enzyme linked immunospot assay; in vivo; mRNA Expression; man; mouse model; mutant; pathogen; polysaccharide C-substance (Streptococcus); programs; prophylactic; research study; response; stem

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.

描述（由申请人提供）：由于易感个体无法产生适当的抗多糖抗体反应以及较小程度的表面蛋白抗体反应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了解。该提议源于并聚焦于我们最近的发现，即 RANTES（调节正常 T 细胞表达和分泌的激活）显着但有差异地增强粘膜和全身免疫。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/适应性识别反应期间，RANTES mRNA 粘膜表达升高，这表明 RANTES 对于肺炎链球菌感染的保护性粘膜免疫至关重要。导致表达减少的 RANTES、MIP-1α 和 CCR5 多态性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 的小鼠携带模型中，RANTES 阻断导致肺炎球菌携带转变为致命性肺炎。这些发现提供了支持以下假设的基本原理：RANTES 对于诱导针对肺炎链球菌的保护性粘膜和全身适应性免疫至关重要。 我们强调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。目标一将评估正常、RANTES 或 T 细胞阻断小鼠对 EF3030 攻击的识别阶段宿主免疫反应。目标二将表征在对照 Ab 治疗或 RANTES 抑制的小鼠患肺炎球菌疾病期间，对 C-多糖 (PC) 的磷酸胆碱决定簇和肺炎球菌表面粘附素 A (PsaA) 的适应性（激活/效应阶段）粘膜和全身免疫反应。目标三将确定 RANTES 在防止野生型、突变表面蛋白（例如 psaA-）和粗糙 EF3030 菌株诱导的携带和/或肺炎中的作用。这项研究将提供有关 RANTES 用于诱导针对肺炎球菌的保护性免疫的细胞和分子机制的重要新信息。