Natural Immunity Against Chlamydia trachomatis

描述(申请人提供)：沙眼衣原体感染是妇女不孕和异位妊娠的主要原因。感染通常是无症状的，导致缺乏检测，疾病风险增加，治疗延误。尽管抗生素治疗可以消除感染，但它不能减轻或逆转既定的破坏性病理。因此，迫切需要一种以疫苗形式的有效预防方法。理性 疫苗设计需要了解与保护性免疫相关的适应机制，并确定最能激发保护性反应的衣原体抗原。动物模型和人类流行病学数据表明，反复接触将最终防止再次感染。通过减毒衣原体突变体解决感染可以预防生殖器和眼部疾病，这为开发有效的衣原体疫苗提供了证据。小鼠模型和人类数据表明，产生干扰素的衣原体特异性γ(Th1)细胞是保护性免疫的主要介质。我们已经确定了衣原体蛋白，它主要诱导CD4T细胞产生干扰素-γ，并且在一组性行为高度活跃的女性中与预防衣原体再感染显著相关。衣原体盆腔炎妇女的转录图谱显示与T细胞生长、增殖和信号转导有关的基因失调。这些数据支持我们的中心假设，即保护依赖于抗原特异性CD4T细胞反应的产生。我们的总体目标是验证我们的新型疫苗候选抗原，分析识别这些抗原的T细胞，并确定导致有效抗衣原体免疫反应的局部和系统反应。我们的基本原理是，识别T细胞效应器活性和与保护相关的抗原将促进疫苗的开发。我们将通过完成以下特定目标来验证我们的中心假设：1.识别与抵抗再感染相关的衣原体抗原的CD4和CD8T细胞的特征。我们将使用多参数流式细胞术、多重细胞因子和mRNA分析来验证这一假设，即在受保护的女性中诱导了多功能的中枢和效应器记忆CD4细胞，而不是CD8 Th1细胞。2.定义可防止再次感染的转录签名。我们将使用子宫内膜RNAseq、全血和细胞微阵列来阐明针对衣原体的保护性适应性免疫反应的演变，并确定疫苗疗效的替代标记物。这项工作的预期结果是与疫苗抗原、T细胞记忆反应和信号通路有关的重要信息，这些信号通路与预防世界上最流行的性传播细菌病原体和可预防失明的主要原因相关。

DESCRIPTION (provided by applicant): Chlamydia trachomatis infection is the leading cause of infertility and ectopic pregnancy in women. Infection is often asymptomatic, leading to lack of detection, increased risk for disease and delay in treatment. Although antibiotic therapy eliminates infection, it does not mitigate or reverse established destructive pathology. Thus, there is a critical need for an effective preventative approach, in the form of a vaccine. Rational vaccine design requires understanding of the adaptive mechanisms associated with protective immunity and identification of chlamydial antigens that best elicit protective responses. Animal models and human epidemiologic data indicate that repeated exposure will ultimately protect against reinfection. Resolution of infection by attenuated chlamydial mutants protects against genital and ocular disease, providing evidence that an effective chlamydial vaccine can be developed. Mouse model and human data indicate that IFN-γ-producing, Chlamydia-specific CD4 (Th1) cells are the primary mediators of protective immunity. We have identified chlamydial proteins that elicit IFN-γ production predominantly from CD4 T cells and are significantly associated with protection against chlamydial reinfection in a group of highly sexually active women. Transcriptional profiling of women with chlamydial pelvic inflammatory disease reveal dysregulation of genes involved in T cell growth, proliferation, and signaling. These data support our central hypothesis that protection is dependent on the generation of antigen-specific CD4 T cell responses. Our overall objectives are to validate our novel vaccine candidate antigens, profile the T cells recognizing these antigens, and determine local and systemic responses that lead to an effective anti- chlamydial immune response. Our rationale is that identification of T cell effector activities and antigens associated with protection will advance the development of a vaccine. We will test our central hypothesis by completing the following specific aims: 1. Characterize CD4 and CD8 T cells recognizing chlamydial antigens associated with resistance to reinfection. We will test the hypothesis that polyfunctional central and effector memory CD4 but not CD8 Th1 cells are induced in protected women, using multiparameter flow cytometry, multiplex cytokine and mRNA analyses. 2. Define a transcriptional signature that leads to protection from reinfection. We will use endometrial RNAseq, whole blood and cellular microarrays to elucidate the evolution of a protective adaptive immune response to Chlamydia and to identify surrogate markers of vaccine efficacy. Expected outcomes of this work are important information related to vaccine antigens, T cell memory responses, and signaling pathways that correlate with protection against the world's most prevalent sexually transmitted bacterial pathogen and a leading cause of preventable blindness.