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Pre-existing SIV Infection Increases Susceptibility to Tuberculosis in Mauritian Cynomolgus Macaques

By Mark A. Rodgers, Cassaundra Ameel, Amy L. Ellis-Connell, Alexis J. Balgeman, Pauline Maiello, Gabrielle L Barry, Thomas C Friedrich, Edwin Klein, Shelby L. O’Connor, Charles A. Scanga

Posted 03 Jul 2018
bioRxiv DOI: 10.1101/361485 (published DOI: 10.1128/iai.00565-18)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the leading cause of death among HIV positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M.tb infection are unknown. We modeled this co-infection in Mauritian cynomolgus macaques (MCM) using SIV as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and six months later co-infected them via bronchoscope with ~10 CFU M.tb. Another eight MCM were infected with M.tb alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial 18F-FDG PET/CT imaging. The eight MCM infected with M.tb alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks post M.tb infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following co-infection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M.tb alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between four and eight weeks post M.tb infection in SIV+, but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M.tb dissemination. At necropsy, animals with pre-existing SIV infection had more extrapulmonary TB disease, more overall pathology, and increased bacterial loads than animals infected with M.tb alone. We thus developed a tractable MCM model in which to study SIV-M.tb co-infection and demonstrate that pre-existing SIV dramatically diminishes the ability to control M.tb co-infection.

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