Impact of HIV infection on early responses to TB exposure

项目总结/文摘

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.