Impact of HIV infection on early responses to TB exposure

项目摘要/摘要 这份K23提案概述了一个5年的职业发展计划和研究战略，将使SARA 她在全球结核病/艾滋病毒研究和临床流行病学方面的背景，并获得了 在前瞻性临床研究、高级生物统计学、T细胞和肺部免疫学方面的关键培训。 作为一名临床研究人员实现独立，作为一名执业肺科医生和 在结核病-艾滋病毒混合感染的流行病学和免疫学后果方面的专业知识，Auld博士要求进一步 在以下方面进行培训：1)招募和管理未来队列，特别是在#年进行临床研究 资源有限的国际环境；2)先进的统计数据，包括能够进行的多级回归分析 调整家庭和个人水平的特征；以及3)翻译免疫学，重点是 结核病暴露的T细胞和肺免疫反应。Auld博士概述了教学课程的计划 并组建了一个多学科的指导团队。她的主要导师是尼尔·甘地博士，他是 临床流行病学和开展全球结核病/艾滋病毒研究。她的合作导师是谢丽尔·戴博士， 兰斯博士，翻译免疫学家，在人类T细胞免疫学方面对结核病/艾滋病毒混合感染具有专门知识 沃勒是一名生物医学统计学家，在公共卫生研究方面有数十年的经验，大卫·吉多博士是一名 著名的肺部临床科学家，有一个强有力的研究计划，探索艾滋病毒介导的肺损伤和 肺泡巨噬细胞功能障碍。 在K23奖项的支持下，Auld博士将解决艾滋病毒感染如何影响 对结核病暴露的反应。她将首先利用埃默里/纽约大学筛查协议产生的数据 结核病研究股(TBRU；U19 AI111211)，以确定艾滋病毒如何影响结核病感染的获得 肯尼亚基苏木结核病患者的家庭接触(目标1)。下一步，促炎、抗炎、 由结核特异性T细胞产生的炎性和调节性细胞因子，以及这些细胞的表型将 比较感染和不感染艾滋病毒的家庭接触者(目标2)。最后，肺免疫反应对 将使用支气管镜检查对感染和未感染艾滋病毒的人的结核病进行单独的队列研究 佐治亚州亚特兰大(目标3)。从这项研究中获得的知识将转化为干预措施，以降低 结核病感染和改善艾滋病毒携带者的长期结果。这项研究直接回应了2016年 美国国立卫生研究院艾滋病研究办公室的优先领域，该办公室考虑与艾滋病毒相关的合并症，如结核病 成为一个高度优先的话题。埃默里大学提供卓越的智力和协作环境 这项研究。凭借她之前的研究经验和培训，TBRU久负盛名的研究 在肯尼亚西部的项目，以及通过课程作业和专家指导进行的方法论培训，Auld博士很好 定位于实现建议的目标，并最终申请专注于探索的R01奖 在结核病/艾滋病毒混合感染的高负担环境下，肺部对结核病暴露的反应。

Project Summary/Abstract This K23 proposal outlines a 5-year career development plan and research strategy that will enable Sara Auld, MD, MSc, to build on her background in global TB/HIV research and clinical epidemiology and gain critical training in prospective clinical research, advanced biostatistics, and T cell and pulmonary immunology. To achieve independence as a clinical investigator with a unique niche as a practicing pulmonologist and an expertise in the epidemiologic and immunologic consequences of TB-HIV coinfection, Dr. Auld requires further training in: 1) recruitment and management of prospective cohorts, specifically the conduct of clinical studies in resource-limited international settings; 2) advanced statistics, including multilevel regression analyses capable of adjusting for household and individual-level characteristics; and 3) translational immunology, with a focus on T cell and pulmonary immune responses to TB exposure. Dr. Auld has outlined a plan of didactic coursework and assembled a multidisciplinary mentorship team. Her primary mentor is Dr. Neel Gandhi, an expert in clinical epidemiology and the conduct of global TB/HIV research. Her co-mentors are Dr. Cheryl Day, a translational immunologist with an expertise in human T cell immunology in TB/HIV coinfection, Dr. Lance Waller, a biomedical statistician with decades of experience in public health research, and Dr. David Guidot, a renowned pulmonary clinician scientist with a robust research program exploring HIV-mediated lung injury and alveolar macrophage dysfunction. With the support of this K23 award, Dr. Auld will address the question of how HIV infection impacts the response to TB exposure. She will first leverage data generated by the screening protocols of the Emory/NYU TB Research Unit (TBRU; U19 AI111211) to determine how HIV affects the acquisition of TB infection among household contacts of TB patients in Kisumu, Kenya (Aim 1). Next, levels of pro-inflammatory, anti- inflammatory, and regulatory cytokines generated by TB-specific T cells, and the phenotype of those cells will be compared for household contacts with and without HIV (Aim 2). Finally, pulmonary immune responses to TB will be compared for people with and without HIV using research bronchoscopy in a separate cohort in Atlanta, GA (Aim 3). Knowledge gained from this study will translate into interventions to decrease the risk of TB infection and improve long-term outcomes for people with HIV. This research responds directly to the 2016 priority areas of the NIH Office of AIDS Research, which considers HIV-associated comorbidities such as TB to be a high priority topic. Emory University provides an exceptional intellectual and collaborative environment for this research. By building upon her prior research experience and training, the well-established TBRU research program in western Kenya, and methodologic training via coursework and expert mentorship, Dr. Auld is well positioned to accomplish the proposed aims and, ultimately, to apply for an R01 award focused on exploring the pulmonary response to TB exposure in a setting with a high burden of TB/HIV coinfection.