PROJECT SUMMARY / ABSTRACT Candidate. Dr. Kathryn Dupnik is an Infectious Disease-trained physician-scientist committed to translational research on mycobacterial diseases. She documented the transcriptome profile of the pathologic immune reactions of leprosy and co-authored 20 peer-reviewed publications on infectious diseases of resource-limited settings. As an investigator with the TB Research Unit, she established the infrastructure for enrollment and monitoring of cohorts for study of Mycobacterium tuberculosis infection. Career Development Plan. Dr. Dupnik’s long-term goal is to become an independent physician-scientist conducting translational laboratory research on the host immune response to mycobacterial pathogens. Her short- and long-term objectives are: 1. To gain skills in clinical epidemiology and the conduct of large clinical cohort studies 2. To gain laboratory expertise in the study of human macrophages and M. tuberculosis 3. To acquire skills in bioinformatics and statistical analysis of large transcriptional data sets 4. To transition to independent investigator by preparing a R01 grant and gaining leadership and mentorship skills. Environment. The proposed research and training will be at Weill Cornell Medical College (New York, NY) and at GHESKIO centers (Port-au-Prince, Haiti). These institutions have a 35-year history of collaboration to provide clinical care and conduct patient-oriented research on HIV, which Dr. Dupnik first joined in 2006. Research. This research is an extension of Dr. Dupnik’s prior work on human immune response to mycobacterial infection. TB recurrence risk is well-documented in the study population in Haiti. The aims of this grant are designed to characterize this population at risk and to identify potential patient-oriented therapies. Specific Aim 1. Characterize macrophages from HIV-infected people with history of at least 2 clinical episodes of pulmonary TB. We will study macrophages derived from peripheral blood mononuclear cells (PBMC) of 50 HIV-infected people with history of multiple episodes of TB and compare them to 50 HIV-infected people from the same community who have had one episode of TB without recurrence. The primary hypothesis is that mycobacterial load in macrophages after in vitro M. tuberculosis infection will be higher in people who had TB recurrence. We will compare gene expression in the M. tuberculosis-exposed macrophages. Specific Aim 2. Determine immune correlates for recurrent TB in a prospectively monitored cohort of HIV- infected patients with TB. We will follow 500 HIV-infected patients with TB for 3 years after TB cure, anticipating that 40 patients will have a reinfection with a new strain of M. tuberculosis. The primary hypothesis is that whole blood from these 40 patients will have a transcriptome profile at cure of first TB which is distinct from people who do not develop recurrent TB, which could be used to target secondary prophylaxis. Significance. Patient oriented...