Syphilis Immunology and Biology to Improve Clinical Management and Vaccine Design

梅毒免疫学和生物学改善临床管理和疫苗设计

• 批准号: 10239030
• 负责人: Carlos F. Caceres
• 金额: $ 62.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239030
• 关键词: Accounting; Antibodies; Antibody Response; Antigens; Area; Bacteria; Biological; Biological Assay; Biological Specimen Banks; Biology; Cardiovascular Diseases; Cell Count; Clinical; Clinical Management; Clinical Research; Collaborations; Detection; Development; Diagnosis; Diagnostic; Diagnostic Reagent Kits; Disease; Early Diagnosis; Enrollment; Enzyme Immunoassay; Epidemiologic Factors; Epidemiology; Epitopes; Evaluation; Funding; Gene Expression; Genotype; Globus Pallidus; Grant; HIV; HIV Infections; Human; Immune; Immune response; Immunoassay; Immunologics; Immunology; Immunosuppression; Incidence; Individual; Infection; Inflammatory; Laboratories; Laboratory Research; Ligands; Lipopolysaccharides; Lipoproteins; Liquid substance; Longitudinal cohort study; Membrane Proteins; Methods; Modeling; Modernization; Molecular; Molecular Biology; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; National Institute of Mental Health; Neurologic; Oral mucous membrane structure; Outcome; Participant; Pathogenesis; Patients; Peru; Positron-Emission Tomography; Program Development; Property; Prospective Studies; Protocols documentation; Reagins; Recording of previous events; Research; Research Infrastructure; Resistance; Serology; Serum; Sexual Health; Specimen; Syphilis; Testing; Time; Tissue-Specific Gene Expression; Toll-like receptors; Treponema; Treponema pallidum; United States; United States National Institutes of Health; Vaccine Design; Viral Load result; World Health Organization; antimicrobial; base; biobank; clinical epidemiology; clinical practice; cohort; cytokine; detection method; evaluation/testing; immune activation; improved; innovation; insight; men; mortality; novel; point of care; point-of-care diagnostics; preventive intervention; programs; rapid test; recruit; response; self testing; seropositive; therapy development; transgender women; vaccine development

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.

项目摘要 这项拟议的研究将有助于大大推进对免疫学，生物学和检测的理解。 通过研究在梅毒高度流行的秘鲁利马新发现的病例，梅毒 仍然是一种严重的疾病，具有显著的不良临床结局，包括神经系统、眼科和 心血管疾病此外，尽管密螺旋体的生物学研究已有100多年， 关于梅毒的病原体-苍白球，最近用现代生物学方法做的很少。 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 授予，“PICASSO研究”（NIH/NIAID 5 R 01 AI 09972），以更深入地研究人类宿主免疫 响应T。梅毒，并填补关键空白的理解梅毒。 我们的建议有三个具体目标。目的1：临床流行病学-假设那些 新发与重复梅毒感染将显示不同的免疫学特征，我们将进行一项 梅毒病例的前瞻性研究，比较有和没有既往梅毒感染史的病例。我们将 a）招募、治疗和随访100名既往未感染梅毒的患者（最近TP血清阴性） 和100个重复梅毒感染的个体（最近TP血清阳性）; B）比较 这2个队列中随时间推移的免疫生物学应答，包括RPR和TPPA滴度，原型 炎性血清细胞因子和免疫表位血清TP抗体测定， 感染状况、CD 4 T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 血清固定状态时的抗体表达与RPR滴度相似的新感染者之间的抗体表达。 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抗体反应）将在个体之间不同， 反复感染与新发梅毒感染、活动性感染与经治感染、HIV相关 免疫抑制和TP菌株类型，我们将调查是否存在关系，在早期梅毒 TP中的差异基因表达、对密螺旋体抗原的免疫应答的发展、宿主 疾病发病机制和感染的免疫相关性的细胞因子谱。目标3：快速测试评估- 使用我们目前的生物样本库（n > 3000份来自一期和二期梅毒的血清学和临床标本- 诊断患者）和目标1中研究参与者的新标本，我们将评估新的快速双重 艾滋病毒/梅毒快速检测，包括RPR/TP联合检测、梅毒螺旋体自测试剂盒和10分钟口服 粘膜液密螺旋体快速试验 这一创新项目将有助于加速梅毒研究和潜在的全球临床实践， 阐明了对梅毒免疫学的新见解，并增加了早期检测和临床治疗的机会。 管理，同时告知疫苗开发。