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

耐多药结核病和艾滋病毒：菌株的组成和治疗反应的生物标志物

• 批准号: 10646233
• 负责人: Patrick George Tobias Cudahy
• 金额: $ 13.79万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646233
• 关键词: Acute-Phase Proteins; Adherence; Antibiotic Resistance; Autopsy; Award; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biopsy; Blood; Cessation of life; Clinical Research; Clinical Sciences; Clinical Skills; Collaborations; Complex; Core Biopsy; Country; Diagnosis; Disease; Drug resistance; Drug resistance in tuberculosis; Early identification; Early treatment; Epidemiology; Event; Faculty; Failure; Fibrinogen; Genetic Variation; Genomics; Genotype; HIV; HIV/TB; Incidence; Individual; Infection; International; Interruption; Intervention; Investigation; Kidney; Laboratory Scientists; Liver; Longitudinal cohort; Lung; Measures; Mentored Research Scientist Development Award; Mentors; Mentorship; Modification; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Mycobacterium tuberculosis complex; Organ; Outcome; Participant; Patient-Focused Outcomes; Patients; Pattern; Persons; Population; Positioning Attribute; Postdoctoral Fellow; Province; Public Health Schools; Regimen; Reporting; Research; Research Personnel; Resistance; Resource-limited setting; Risk; Sampling; Scientist; Series; Serum; Site; South Africa; South African; Specimen; Spleen; Sputum; Techniques; Time; Tissues; Training; Treatment Effectiveness; Treatment Failure; Treatment outcome; Tuberculosis; United States; Work; career; clinical diagnostics; clinically relevant; co-infection; cohort; early detection biomarkers; epidemiology study; experience; follow-up; genome sequencing; genomic epidemiology; hepcidin; high risk; improved; innovation; insight; lymph nodes; microbial disease; microbiome; mid-career faculty; mortality; next generation sequencing; novel; participant enrollment; pathogen; patient population; patient subsets; prevent; response; tenure track; therapy design; tool; trafficking; transmission process; treatment duration; treatment response; trend; tuberculosis treatment; whole genome

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.

项目概要/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 和南非。 Cudahy 博士的研究重点是多种药物患者的流行病学和结果 耐药结核病（MDR-TB）和艾滋病毒合并感染。他在该地区工作了十多年， 过去 30 个月全职工作。他的研究地点位于南非夸祖鲁-纳塔尔省，具有很高的研究价值。 耐多药结核病和艾滋病毒合并感染的发生率以及治疗失败率和死亡率很高。拟议的 研究需要开发特征明确的纵向队列并与国内合作 实验室科学家应用临床诊断和创新基因组技术。其目标有三个 提案：1) 寻找 HIV 和 MDR 合并感染患者的结核治疗反应标志物 结核病； 2) 描述结核分枝杆菌感染的宿主内复杂性对耐多药结核病治疗的影响 HIV合并感染者的结果； 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，并在治疗的前 16 周内进行系列血液和痰检测 治疗。通过这些研究，Cudahy 博士将推进他在临床和基础科学研究方面的培训。 资源有限的环境，获得临床和流行病学研究的分析和生物统计学技能，以及 发展生物信息学方面的专业知识。他将在美国导师 Dr. Dr. 的指导下开展该项目。 Theodore Cohen，耶鲁大学公立学院微生物疾病流行病学副教授 Health，其研究重点是耐药结核分枝杆菌的出现和传播。他有 曾指导2名获得K系列奖项的学员和6名获得K系列奖项的博士后 成功竞争终身教授职位。 Cudahy 博士的南非导师是 Douglas 博士 Wilson 是一位临床医生和卓有成就的研究人员，在进行这两项研究方面拥有超过 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。此外，大卫博士 TGen North 病原体和微生物组联合主任兼副教授 Engelthaler 表示 开发了用于基因组流行病学的新型基因分型技术，并将提供下一代的专业知识 测序工具。这项研究的结果将构成 R01 应用评估的基础 基于治疗反应标志物和多菌株 M 证据的干预策略。 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的共同作用 感染，并有助于设计可以改善患者治疗结果的干预措施。