PROJECT SUMMARY/ABSTRACT Candidate. Dr. Jyoti Mathad is an Infectious Diseases-trained physician-scientist who has spent the past five years conducting research in India. She helped establish a cohort of pregnant women, developed strong scientific collaborations with Indian scientists, trained an Indian research team, and authored 8 publications related to her research. She has documented that the immune changes that occur in pregnancy impact the performance of tests to detect latent tuberculosis (TB) infection. She hypothesizes that these changes contribute to the documented increase in active TB incidence in postpartum women. Career Development Plan. Dr. Mathad’s immediate and long-term goals are the following: 1) To determine the impact of pregnancy on the host immune response to M. tuberculosis 2) To conduct a longitudinal study to identify immune correlates during pregnancy that predict the development of active TB in postpartum HIV-infected women 3) To become an expert in the pathogenesis of infectious diseases in pregnant women by gaining knowledge in translational laboratory science in immunology and statistical analysis of large data sets. 4) To become an independent physician-scientist, using the knowledge and training obtained during this grant period to design and submit an R01 proposal in year 4 of this grant 5) To become a mentor to young investigators in the US and India Dr. Mathad will develop these skills through coursework and the implementation of her research in India. Environment. The proposed research and training will take place at Weill Cornell Medical College (USA), at Byramjee Jeejeebhoy Medical College (India) and the National Institute for Research in Tuberculosis (India). The collaborations between these institutions will provide Dr. Mathad with strong mentorship. Research. Each year, over 200,000 pregnant and postpartum women worldwide develop active TB. Understanding the immunologic mechanisms by which pregnancy increases the risk of developing active TB has important implications for disease prevention strategies for pregnant women and their children. Aim 1: Compare the host immune responses to M. tuberculosis in 600 pregnant and non-pregnant women in Pune, India. This aim will test the hypothesis that pregnant women have an increased abundance of regulatory immune cells (CD4+CD25+Foxp3+) and cell products (TGF-, IL-10) and a decrease in helper T cells and their products (IFN-, IL-2) after ex vivo stimulation of PBMCs collected in the late 3rd trimester with M. tuberculosis antigens. Dr. Mathad will enroll both HIV-infected (n=300) and –uninfected (n=300) women. Aim 2: Identify the immune correlates that predict active postpartum TB in a cohort of 300 HIV-infected pregnant women. The primary hypothesis is that the magnitude of decrease in IFN- and other cell-mediated immune cytokines during the 3rd trimester will correlate with the development of active TB in the first postpartum year.