Tuberculosis (TB) remains among the leading causes of death from infectious disease worldwide, and its significance in the developed world may be heightened by the emergence of extreme drug-resistant strains. Most active TB disease in adults arises by reactivation of latent TB infection (LTBI) that may be harbored for decades without illness or risk of transmission. While clear associations exist between TB and HIV/AIDS, immunosuppressive therapies, or certain rare mutations in genes of the immune system, the factors promoting TB susceptibility and the reactivation of LTBI in the general population are not well understood. We discovered that infection of mice with lymphocytic choriomeningitis virus (LCMV), human pathogen, increases TB susceptibility and alters the pattern of immunopathology in the lung. This susceptibility persists for many months after LCMV exposure and at time points when no replication-competent virus or anatomical injury persists in the lung. We believe that this models the potential influence of virus infections on human TB susceptibility. This R21 application seeks funding for experiments testing the hypothesis that crossreactive LCMV-specific CD8+ memory T cells interfere with the expression of adaptive immunity to Mycobacterium tuberculosis (Mtb) in the lung, and experiments testing competing mechanistic hypotheses. We plan to generate data that will support a broader R01 proposal investigating interactions between anti-viral and anti-mycobacterial immunity that impact TB susceptibility. This topic is significant not only in terms of acquired risk factors for TB but also in the investigation of host defense in sequential infection. No human patients are immunologically naive, yet the majority of infectious disease studies in animal models employ naive hosts. PROJECT NARRATIVE. Only about 1 in 20 people infected with a germ that causes tuberculosis go on to become sick with tuberculosis. It remains unknown why some apparently healthy people develop TB while many other do not. This project studies how a particular virus infection might make people more prone to TB.