Schistosomiasis, Mucosal Immunity, and HIV Susceptibility

描述(由申请人提供)：詹妮弗·唐斯博士是一名受过传染病培训的内科科学家，长期致力于在一个资源匮乏的国家进行以患者为导向的研究。在过去的6年里，她一直在坦桑尼亚工作，在那里她掌握了流利的斯瓦希里语，与坦桑尼亚科学家开展了合作，培训了一个坦桑尼亚研究团队，并撰写了14本与她的研究和临床研究有关的同行评议出版物。她记录了800多名农村妇女中艾滋病毒感染和血吸虫病之间的高度显著的联系，这构成了这一申请的基础。唐斯博士将寻求以下领域的额外培训：1)在国际环境下进行复杂的临床和翻译研究，以及2)使用和应用原理和 先进的统计方法和免疫学的工具。她将通过在坦桑尼亚农村实施她的研究建议和课程工作来发展这些技能。唐斯博士的近期和长期目标如下：1)开展一项前瞻性研究，量化血吸虫感染者感染艾滋病毒的几率。目标是利用这些证据扩大血吸虫病的治疗，这可能会对减少艾滋病毒传播产生重大影响。2)了解血吸虫病患者HIV易感性增强的免疫发病机制，特别是与宫颈黏膜中CD4+Th17细胞的作用有关。3)在翻译实验室科学和先进的统计方法方面积累经验和对话。4)成为一名独立的内科科学家，利用在这一资助期间获得的知识和培训，在这笔资助的第四年设计并提交R01提案。5)成为美国和坦桑尼亚年轻调查人员的导师。环境拟议的研究和培训将在威尔康奈尔医学院(纽约)、威尔-布甘多医学中心和国家医学研究所(坦桑尼亚姆万扎)进行。这些机构之间的伙伴关系提供了一个独特的合作环境，支持纽约和坦桑尼亚以患者为导向的研究。纽约的医学院和坦桑尼亚的医疗中心以威尔的名字命名，以表彰桑福德和琼·威尔的慈善事业。研究。这项研究将建立在唐斯博士先前在坦桑尼亚所做工作的基础上，并对携带血结核沙门氏菌的男性和女性感染艾滋病毒的几率进行量化(目标1)。唐斯博士之前的发现导致了我们对血吸虫病如何增加艾滋病毒感染易感性的理解的范式转变，这将在目标2中进一步探索。目标1：通过对坦桑尼亚农村地区3万人的既定队列进行嵌套的病例对照研究，确定患有慢性血吸虫病的成年人与未感染血吸虫病的对照组相比，感染艾滋病毒的几率比。这一目标将检验最初的假设，即感染嗜血杆菌使艾滋病毒感染发生率增加50%，从每100人年感染0.8人增加到1.2人。队列参与者每六个月收集一次血点进行艾滋病毒检测，并将其存入银行。我们将检测HIV血清转换者(病例)的库中血点是否患有血吸虫病，并将其与通过发病率密度抽样选择的对照进行比较。第二个假设是，感染艾滋病毒的几率将与血吸虫感染的程度相关。目的：探讨血吸虫病流行村HIV抗体阴性妇女宫颈粘膜刷检、活检和外周血中包括Th17细胞在内的CD4+T细胞基因表达和频率的变化。由于对宫颈粘膜取样的可行性，这些研究将仅在妇女中进行。初步的假设是，患有血吸虫病的妇女宫颈粘膜中CD4+Th17细胞产物和标志物的mRNA表达水平是非血吸虫病妇女的2倍。第二个假设是，抗原提呈细胞和促炎细胞因子的基因表达将增加，基因表达将与外周血和宫颈活检结果以及血吸虫感染的程度相关。我们将使用共聚焦显微镜来评估CD4+T细胞类型及其在宫颈粘膜组织中的分布。我们还将进行流式细胞术，以确定外周血中包括Th17细胞在内的CD4+T细胞的频率，并将其与粘膜研究相关联。此外，我们将确定在12个月的随访中，吡喹酮治疗该队列中的血吸虫病感染是否会使粘膜中CD4+Th17基因的表达减少至少50%。

DESCRIPTION (provided by applicant): Dr. Jennifer Downs is an Infectious Diseases-trained physician-scientist with a longstanding commitment to patient-oriented research in a resource-poor country. She has been based in Tanzania for the past 6 years, where she has become fluent in Kiswahili, developed collaborations with Tanzanian scientists, trained a Tanzanian study team, and authored 14 peer-reviewed publications related to her research and clinical studies. She has documented a highly-significant association between HIV infection and schistosomiasis in over 800 rural women, which forms the basis for this application. Dr. Downs will seek additional training in the following areas: 1) the conduct of a complex clinical and translational study in an international setting, and 2) the ability to use and apply principles and tools of advanced statistical methods and immunology. She will develop these skills through the implementation of her research proposal in rural Tanzania and coursework. Dr. Downs's immediate and long-term goals are the following: 1) to conduct a prospective study to quantitate the odds of HIV infection in individuals with Schistosoma haematobium. The goal is to use this evidence to expand schistosomiasis treatment, which could have a major effect on reducing HIV transmission. 2) To understand the immunopathogenesis of enhanced HIV susceptibility in schistosomiasis patients specifically related to the roles of CD4+ Th17 cells in the cervical mucosa. 3) To gain experience and conversance in translational laboratory science and advanced statistical methods. 4) To become an independent physician-scientist using the knowledge and training obtained during this grant period to design and submit an R01 proposal during year 4 of this grant. 5) To become a mentor to young investigators, both in the US and in Tanzania. Environment. The proposed research and training will take place at Weill Cornell Medical College (New York) and at the Weill-Bugando Medical Centre and the National Institute for Medical Research (Mwanza, Tanzania). The partnerships between these institutions provide a unique collaborative environment that supports patient-oriented research in both New York and Tanzania. The medical college in New York and the medical center in Tanzania bear the name Weill in recognition of the philanthropy of Sanford and Joan Weill. Research. This research will build on Dr. Downs's prior work in Tanzania and quantitate the odds of HIV acquisition in both men and women with S. haematobium (Aim 1). Dr. Downs's prior findings led to a paradigm shift in our understanding of how schistosomiasis may increase susceptibility to HIV infection, which will be further explored in Aim 2. Aim 1: To determine the odds ratio of HIV infection in adults with chronic S. haematobium compared to controls without schistosomiasis through the conduct of a case-control study nested within an established cohort of 30,000 people in rural Tanzania. This aim will test the primary hypothesis that S. haematobium infection increases the incidence of HIV infection by 50%, from 0.8 to 1.2 infections per 100 person-years. Cohort participants have blood spots collected for HIV testing which are banked every six months. We will test banked blood spots of HIV seroconverters (cases) for schistosomiasis and compare this to controls selected by incidence density sampling. A secondary hypothesis is that the odds of HIV infection will correlate with the magnitude of schistosome infection. Aim 2: To determine the effect of S. haematobium infection on the gene expression and frequency of CD4+ T cells, including Th17 cells, in the cervical mucosa brushings, biopsies, and in the peripheral blood of HIV-seronegative women recruited from villages endemic for S. haematobium. These studies will be conducted only in women because of the feasibility of sampling the cervical mucosa. The primary hypothesis is that the cervical mucosa of women with schistosomiasis will have 2-fold greater mRNA expression of CD4+ Th17 cell products and markers than will women without schistosomiasis. Secondary hypotheses are that gene expression of antigen-presenting cells and pro-inflammatory cytokines will be increased, and that gene expression will correlate with the peripheral blood and cervical biopsy findings and with the magnitude of the schistosome infection. We will use confocal microscopy to assess CD4+ T cell types and their distribution within the cervical mucosal tissue. We will also perform flow cytometry to determine frequencies of CD4+ T cells, including Th17 cells, in peripheral blood and to correlate this with mucosal studies. In addition, we will determine if praziquantel treatment of the schistosomiasis infection in this cohort will decrease mucosal CD4+ Th17 gene expression by at least 50% over 12 months of follow-up.