Multidrug-resistant tuberculosis and HIV: Composition of Strains and biomarkers of treatment response

项目摘要/摘要 申请福格蒂国际研究科学家发展奖是为了支持帕特里克博士 Cudahy在美国科学家的指导下走向独立的临床研究生涯 还有南非。库达希博士的研究重点是多药耐药患者的流行病学和预后。 耐药结核病(耐多药结核病)和艾滋病毒混合感染。他在该地区工作了十多年， 过去30个月的全职工作。他在南非夸祖鲁-纳塔尔省的研究地点有很高的 耐多药结核病和艾滋病毒混合感染的发生率和治疗失败率和死亡率都很高。建议数 研究将需要开发具有良好特征的纵向队列，并与国内合作 实验室科学家应用临床诊断学和创新的基因组技术。有三个目标 建议：1)在同时感染HIV和MDR的患者中寻找结核病治疗反应的标志物- 2)描述结核分枝杆菌感染宿主内复杂性对耐多药结核治疗的影响 3)描述结核分枝杆菌宿主内的空间多样性 在耐多药结核病治疗期间死亡的艾滋病毒合并感染者体内的菌株。Cudahy博士将招募参与者 在耐多药结核病治疗开始时，并在接下来的前16周内进行一系列的血液和痰分析 治疗。通过这些研究，Cudahy博士将提高他在临床和基础科学研究方面的培训 在资源有限的情况下，获得临床和流行病学研究的分析和生物统计技能，以及 发展生物信息学方面的专业知识。他将在他的美国导师Dr。 耶鲁大学公共学院微生物疾病流行病学副教授西奥多·科恩 其研究重点是耐药结核分枝杆菌的出现和传播。他有 此前曾指导过两名获得K系列奖的实习生和6名博士后研究员 成功竞争终身教职。库达希博士的南非导师是道格拉斯博士 威尔逊是一位临床医生和有成就的研究人员，他在这两个领域都有超过15年的经验 南非结核病和艾滋病毒的纵向临床和流行病学研究。另外，大卫博士 恩格尔塔勒，TGen North病原体和微生物组部门的联席主任兼副教授 为基因组流行病学开发了新的基因分型技术，并将在下一代中提供专业知识 测序工具。这项研究的结果将成为R01应用程序进行评估的基础 基于治疗反应标志物和多重M株证据的干预策略。 肺结核感染。最终，这项工作将使人们更好地了解耐多药结核病和艾滋病毒共同 它还有助于设计可改善患者预后的干预措施。

PROJECT SUMMARY/ABSTRACT This application to the Fogarty International Research Scientist Development Award is to support Dr. Patrick Cudahy towards an independent clinical research career under mentorship from scientists in the United States and South Africa. Dr. Cudahy’s research focuses on the epidemiology and outcomes of patients with multidrug- resistant tuberculosis (MDR-TB) and HIV co-infection. He has worked in the region for the over ten years, and full-time for the past 30 months. His research site in the KwaZulu-Natal province of South Africa has a high incidence of MDR-TB and HIV co-infection with high rates of treatment failure and mortality. The proposed research will require developing well characterized longitudinal cohorts and collaborating with in-country laboratory scientists to apply clinical diagnostics and innovative genomic techniques. There are three aims of the proposal: 1) To find markers of tuberculosis treatment response in patients co-infected with HIV and MDR- TB; 2) To describe the impact of within-host complexity of M. tuberculosis infection on MDR-TB treatment outcomes in HIV-coinfected individuals; and 3) To describe the within-host spatial diversity of M. tuberculosis strains within HIV-coinfected individuals dying during treatment for MDR-TB. Dr. Cudahy will enroll participants at the start of MDR-TB therapy and follow them with serial blood and sputum assays for the first 16 weeks of treatment. Through these studies, Dr. Cudahy will advance his training in clinical and basic science research in resource limited settings, acquire analytical and biostatistics skills for clinical and epidemiologic research, and develop expertise in bioinformatics. He will conduct the project under the guidance of his U.S. mentor, Dr. Theodore Cohen, Associate Professor of Epidemiology of Microbial Diseases at the Yale School of Public Health, whose research focuses on the emergence and spread of drug-resistant M. tuberculosis. He has previously mentored two trainees that have received K-series awards and 6 postdoctoral fellows who have successfully competed for tenure-track faculty positions. Dr. Cudahy’s South African mentor is Dr. Douglas Wilson, a clinician and accomplished researcher who has over 15 years’ experience in conducting both longitudinal clinical and epidemiological studies of tuberculosis and HIV in South Africa. Additionally, Dr. David Engelthaler, Co-Director and Associate Professor of the Pathogen and Microbiome Division at TGen North has developed novel genotyping techniques for genomic epidemiology and will provide expertise in next-generation sequencing tools. The results of this research will form the basis for an R01 application to evaluate interventional strategies based on markers of treatment response and evidence of multiple strain M. tuberculosis infection. Ultimately, this work will produce a better understanding of MDR-TB and HIV co- infection and contribute to the design of interventions that can improve patient outcomes.