Schistosomiasis, Mucosal Immunity, and HIV Susceptibility

描述（由申请人提供）：Jennifer唐斯博士是一位受过传染病培训的医生兼科学家，长期致力于在资源匮乏的国家开展以患者为导向的研究。过去6年来，她一直在坦桑尼亚工作，在那里她已经能说流利的斯瓦希里语，与坦桑尼亚科学家开展合作，培训了坦桑尼亚研究团队，并撰写了14篇与她的研究和临床研究相关的同行评审出版物。她记录了800多名农村妇女的艾滋病毒感染和血吸虫病之间的高度显着关联，这构成了本申请的基础。唐斯博士将在以下领域寻求额外的培训：1）在国际环境中进行复杂的临床和转化研究，2）使用和应用原则的能力， 先进的统计方法和免疫学工具。她将通过在坦桑尼亚农村实施她的研究计划和课程来发展这些技能。唐斯博士的近期和长期目标如下：1）进行一项前瞻性研究，以定量评估患有埃及血吸虫的个体感染HIV的几率。目标是利用这一证据扩大血吸虫病治疗，这可能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，特别是与宫颈粘膜中CD 4 + Th 17细胞的作用有关。3)获得实验室科学和先进统计方法的经验和知识。4)成为一名独立的物理学家，科学家使用的知识和培训，在此期间获得的补助金，设计和提交R 01的建议，在今年的4补助金。5)成为美国和坦桑尼亚年轻研究人员的导师。环境拟议的研究和培训将在威尔康奈尔医学院（纽约）和威尔-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，支持在纽约和坦桑尼亚以病人为导向的研究。纽约的医学院和坦桑尼亚的医疗中心都以威尔命名，以表彰桑福德和琼·威尔的慈善事业。Research.这项研究将建立在唐斯博士先前在坦桑尼亚的工作基础上，并量化S。（Aim 1）。唐斯博士先前的发现导致了我们对血吸虫病如何增加对HIV感染的易感性的理解的范式转变，这将在目标2中进一步探讨。目的1：确定慢性乙型肝炎患者中HIV感染的优势比。通过在坦桑尼亚农村一个已建立的30，000人队列中进行病例对照研究，将感染血吸虫病的患者与未感染血吸虫病的对照组进行比较。这一目标将检验S.埃及血吸虫感染使艾滋病毒感染的发病率增加50%，从每100人年0.8例增加到1.2例。队列参与者每六个月采集一次用于艾滋病毒检测的血点。我们将检测HIV血清转换者（病例）的血吸虫病库血点，并将其与通过发病密度抽样选择的对照进行比较。第二个假设是，HIV感染的几率与病毒感染的程度相关。目的2：研究S.在宫颈粘膜刷检、活组织检查和外周血中，从流行性出血热流行的村庄招募的HIV血清阴性妇女的基因表达和CD 4 + T细胞（包括Th 17细胞）频率上，埃及血吸虫由于宫颈粘膜取样的可行性，这些研究将仅在女性中进行。主要的假设是，血吸虫病妇女宫颈粘膜的CD 4 + Th 17细胞产物和标记物的mRNA表达比没有血吸虫病的妇女高2倍。次要假设是抗原呈递细胞和促炎性细胞因子的基因表达将增加，并且基因表达将与外周血和宫颈活检结果以及染色体感染的程度相关。我们将使用共聚焦显微镜来评估CD 4 + 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CD 4 + T细胞（包括Th 17细胞）的频率，并将其与粘膜研究相关联。此外，我们将确定吡喹酮治疗血吸虫病感染在这个队列中是否会降低粘膜CD 4 + Th 17基因表达至少50%超过12个月的后续行动。

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.