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: 10189740
• 负责人: Patrick George Tobias Cudahy
• 金额: $ 13.78万
• 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/10189740
• 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; Complex; Core Biopsy; Country; Diagnosis; Disease; Drug resistance; Early identification; Early treatment; Enrollment; Epidemiology; Event; Faculty; Failure; Fibrinogen; Genetic Variation; Genomics; Genotype; HIV; HIV drug resistance; HIV/TB; Immune response; Incidence; Individual; Infection; International; Interruption; Intervention; Investigation; Kidney; Laboratory Scientists; Liver; Longitudinal cohort; Lung; Measures; Mentored Research Scientist Development Award; Mentors; Mentorship; Modification; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Organ; Outcome; Participant; Patient-Focused Outcomes; Patients; Pattern; Population; Positioning Attribute; Postdoctoral Fellow; Province; Public Health Schools; Regimen; Reporting; Research; Research Personnel; Resistance; Resources; 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; base; biomarker identification; 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; 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.

项目总结/摘要 这份福格蒂国际研究科学家发展奖的申请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药耐药患者的流行病学和结果， 耐多药结核病（MDR-TB）和艾滋病毒合并感染。他在该地区工作了十多年， 全职工作了30个月他在南非夸祖鲁-纳塔尔省的研究地点有很高的 耐多药结核病和艾滋病毒合并感染的发生率高，治疗失败率和死亡率高。拟议 研究将需要发展特征良好的纵向队列，并与国内 实验室科学家应用临床诊断和创新的基因组技术。有三个目标 建议：1）寻找结核病治疗反应的标志物，在合并感染HIV和MDR的患者中， 2）描述了M.耐多药结核病治疗中的结核病感染 HIV共感染个体的结果; 3）描述M.结核 耐多药结核病治疗期间死亡的艾滋病毒合并感染者中的菌株。卡达希博士将招募参与者 在开始耐多药结核病治疗时，并在治疗的前16周内对他们进行一系列血液和痰液检测。 治疗通过这些研究，Cudahy博士将在临床和基础科学研究方面继续深造， 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， 发展生物信息学方面的专门知识。他将在他的美国导师博士的指导下进行这个项目。 西奥多科恩，耶鲁大学公共卫生学院微生物疾病流行病学副教授 他的研究主要集中在耐药M。结核他 曾指导过两名获得K系列奖的学员和6名获得 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 威尔逊说，临床医生和有成就的研究人员谁拥有超过15年的经验，进行这两个 南非结核病和艾滋病毒的纵向临床和流行病学研究。另外，大卫医生 Engelthaler是TGen North病原体和微生物组系的联合主任兼副教授， 为基因组流行病学开发了新的基因分型技术，并将为下一代 测序工具。这项研究的结果将构成R 01应用程序的基础， 基于治疗反应标志物和多种菌株M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的共同作用， 感染，并有助于设计干预措施，可以改善病人的结果。