Syphilis Immunology and Biology to Improve Clinical Management and Vaccine Design

项目摘要 拟议的研究将有助于极大地促进对免疫学、生物学和检测的理解。 梅毒，通过研究秘鲁利马新发现的梅毒病例，在那里梅毒高度流行。梅毒 仍然是一种严重的疾病，具有显著的不良临床后果，包括神经、眼科和 心血管疾病。此外，尽管对密螺旋体的生物学研究已有100多年的历史 梅毒的媒介梅毒，最近用现代生物学方法所做的工作很少。 我们的研究建立在通过先前资助的NIH能力建设创建的研究基础设施上 格兰特，《毕加索研究》(NIH/NIAID 5R01AI09972)，更深入地研究人类宿主免疫 对梅毒螺旋体的反应，填补了对梅毒认识的关键空白。 我们的建议有三个具体目标。目标1：临床流行病学-假设那些患有 初发梅毒与反复梅毒感染将表现出不同的免疫学特征，我们将进行 对梅毒病例进行前瞻性研究，比较有无梅毒感染史的患者。我们会 A)招募、治疗和跟踪100名未感染梅毒(最近梅毒螺旋体血清阴性)的梅毒患者 和100名反复梅毒感染者(最近梅毒血清阳性)；b)比较 这两个队列中随时间推移的免疫生物学反应，包括RPR和TPPA效价，典型 炎性血清细胞因子和免疫学表位血清TP抗体检测HIV- 感染状况、CD4T细胞计数和HIV病毒载量。我们还将比较细胞因子谱和新的TP 在RPR效价相近的人群中，血清凝集状态时的抗体表达与新感染时的抗体表达。 目的2：生物学假设临床表现和免疫反应(细胞因子 对TP表面蛋白和脂蛋白的图谱和抗体反应)会因患有 重复感染与新发梅毒感染、活动性感染与治疗感染、艾滋病毒相关感染 免疫抑制和TP毒株类型，我们将调查早期梅毒是否存在这种关系 梅毒螺旋体的差异基因表达与宿主对梅毒螺旋体抗原的免疫应答 疾病发病机制的细胞因子谱和感染的免疫相关性。目标3：快速测试评估- 使用我们目前的生物库(n&gt；3000份一期和二期梅毒的血清学和临床标本- 诊断患者)和来自目标1的研究参与者的新样本，我们将评估新的快速Dual HIV/梅毒快速检测，包括RPR/TP联合检测、梅毒螺旋体自检试剂盒和10分钟口服 黏膜液密螺旋体快速检测。 这一创新计划将有助于加速梅毒研究，并可能在全球范围内进行临床实践， 启发对梅毒免疫学的新见解，增加早期发现和临床机会 管理，同时通知疫苗开发。

PROJECT ABSTRACT The proposed study will help substantially advance understanding of the immunology, biology, and detection of syphilis, through studying newly identified cases of in Lima, Peru, where syphilis is hyper-endemic. Syphilis remains a serious disease with significant adverse clinical outcomes including neurological, ophthalmic, and cardiovascular disease. Furthermore, despite over 100 years of research in the biology of Treponema pallidum, the agent of syphilis, little has been done recently with modern biological methods. Our study builds on the research infrastructure created through a previously-funded NIH capacity-building grant, the “PICASSO Study” (NIH/NIAID 5R01AI09972), to more deeply investigate the human host immune response to T. pallidum, and fill critical gaps in the understanding of syphilis. There are three specific aims to our proposal. Aim 1: Clinical epidemiology — Hypothesizing that those with de novo versus repeat syphilis infection will demonstrate different immunological profiles, we will conduct a prospective study of syphilis cases, comparing those with and without a history of prior syphilis infection. We will a) recruit, treat and follow 100 individuals with incident syphilis without prior infection (recently TP seronegative) and 100 individuals with repeat syphilis infection (recently TP seropositive); b) Compare markers of immunobiologic response over time in those 2 cohorts, including RPR and TPPA titers, prototypical inflammatory serum cytokines, and immunologic epitope serum TP antibody assays accounting for HIV- infection status, CD4 T-cell count and HIV viral load. We will also compare cytokine profiles and novel TP antibody expression at the time of serofast status versus new infection among those with similar RPR titers. Aim 2: Biological — Hypothesizing that the clinical manifestations and immunologic responses (cytokine profiles and antibody responses to TP surface proteins and lipoproteins) will differ between individuals with repeat infection versus de novo incident syphilis infection, active versus treated infection, HIV-associated immunosuppression and TP strain type, we will investigate whether a relationship exists during early syphilis between differential gene expression in TP, development of the immune response to treponemal antigens, host cytokine profiles of disease pathogenesis and immune correlates of infection. Aim 3: Rapid test evaluation — Using our current biobank (n > 3000 serological and clinical specimens from primary and secondary syphilis- diagnosed patients) and new specimens from study participants from Aim 1, we will evaluate new rapid dual HIV/syphilis rapid tests including combination RPR/TP tests, treponemal self-test kits, and a 10-minute oral mucosal fluid treponemal rapid test. This innovative program will help accelerate syphilis research and potentially clinical practice worldwide, illuminating new insights into syphilis immunology and enhancing opportunities for early detection and clinical management, while informing vaccine development.