Uncovering the underlying immune perturbations that determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection

Abstract

Abstract Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection, yet how they alter the pulmonary microenvironment to foster coinfection and worsen disease severity is unclear. We developed a coinfection model in mice with chronic lymphocytic choriomeningitis virus and Mtb coinfection that recapitulated the central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination and heightened mortality. These long-term disease consequences were not due to chronic virus-induced immunosuppression or exhaustion, but instead were determined by early alterations in immune surveillance of Mtb coinfection. Mechanistically, increased chronic virus induced TNFα production initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lung-draining lymph nodes (LNs) and allowing bacterial sanctuary. The inhibited antigen arrival to LNs delayed CD4 T cell priming, allowing Mtb to replicate to higher set-points before T cell mediated control could be initiated. Once primed, Mtb-specific CD4 T cell differentiation skewed away from the Th1 responses associated with Mtb control, and instead toward Th17 differentiation. The elevated IL17 increased pulmonary neutrophil influx that decreased the long-term survival of coinfected mice. Therapeutically correcting the timing of CD4 T cell priming re-established CD4 Th1 over Th17 dominance, diminished pulmonary neutrophilia, and enabled enhanced Mtb control in the presence of chronic viral coinfection. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function and foster long-term coinfection.