Schistosomiasis, Mucosal Immunity, and HIV Susceptibility

点击翻译按钮获取中文摘要

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.