Xu, WenxiSnell, Laura M.Guo, MengdiBoukhaled, GiselleMacleod, Bethany L.Li, MingTullius, Michael V.Guidos, Cynthia J.Tsao, Ming-SoundDivangahi, MaziarHorwitz, Marcus A.Liu, JunBrooks, David G.2024-11-212024-11-212021Xu W, Snell LM, Guo M, et al. Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection. Immunity. 2021;54(3):526-541.e7. doi:10.1016/j.immuni.2021.01.003https://hdl.handle.net/1805/44644Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.en-USPublisher PolicyCD4 T cellsCyTOFLCMVMycobacterium tuberculosisT cell differentiationTh1 cellsTh17 cellsChronic viral infectionCoinfectionNeutrophilArticle