An estimated 1/3 of the world population is already infected with Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), with an almost 5-10% of latent infected patients developing active tuberculosis during their lifetime. In the last three years, infection with severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2, a.k.a. SCV2) the causative agent of COVID-19, has resulted in 6.5 million deaths. According to the WHO Global TB Report 2022, the SCV2 pandemic in 2020-2021 was associated with the reversal of the steady decline in TB death rate for the first time since 2005. Our long-term goal is to better control tuberculosis and manage cases of superinfection with SCV2 as well as gain insight to immunological consequences of SCV2 infection. Preliminary data from our group indicated SCV2 superinfection increased M. tb loads in murine lungs and promoted dissemination to extra-pulmonary organs, which was associated with specific changes in immunomodulatory cytokines (e.g., IFN-g and IL10) and decreased general inflammation in the lungs. These data underpinned our central hypothesis that SCV2 superinfection compromises anti-TB immunity, leading to greater dissemination of M. tb. To address the central hypothesis we plan to I) Characterize the TB/SCV2 superinfection in a latent murine model of TB using C3HeB/FeJ mice in a setup termed Immune Competent TB Model (ICTM); II) Define mechanisms of M. tb dissemination during SCV2 superinfection by targeting IFN-g and IL-10 cytokines using reporter and repletion murine models that are infected with M. tb before superinfection with SCV2 BA.5. Finally, III) Examine M. tb progression in Diversity Outbred (DO) mouse model compared to inbred mice to characterize mycobacterial growth phase associated with pathological and immunological changes during TB/SCV2 superinfection. Outcomes from this project will further improve our understanding of TB immunopathogenesis and how latent infections in humans can convert to active cases of TB including furthering knowledge on the granuloma’s role in containment and pathogenesis. Importantly, gained knowledge could help in understanding TB immunopathogenesis during any future respiratory superinfection, not SCV2 alone. Future research building on outcomes from this project could help in the control of both TB and COVID-19 pandemics that could be tailored for other respiratory emerging infections (e.g. Influenza).