Glutathione Depletion Exacerbates Hepatic <i>Mycobacterium tuberculosis</i> Infection

Extrapulmonary tuberculosis (EPTB) accounts for approximately 17% of all <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>) infections globally. Immunocompromised individuals, such as those with HIV infection or type 2 diabetes mellitus (T2DM), are at an increased risk for EPTB. Previous studies have demonstrated that patients with HIV and T2DM exhibit diminished synthesis of glutathione (GSH) synthesizing enzymes. In a murine model, we showed that the diethyl maleate (DEM)-induced depletion of GSH in the lungs led to increased <i>M.tb</i> burden and an impaired pulmonary granulomatous response to <i>M.tb</i> infection. However, the effects of GSH depletion during active EPTB in the liver and spleen have yet to be elucidated. In this study, we evaluated hepatic GSH and malondialdehyde (MDA) levels, as well as cytokine profiles, in untreated and DEM-treated <i>M.tb</i>-infected wild-type (WT) C57BL/6 mice. Additionally, we assessed hepatic and splenic <i>M.tb</i> burdens and tissue pathologies. DEM treatment resulted in a significant decrease in the levels of the reduced form of GSH and an increase in MDA, oxidized GSH, and interleukin (IL)-6 levels. Furthermore, DEM-induced GSH decrease was associated with decreased production of IL-12 and IL-17 and elevated production of interferon-gamma (IFN-γ), tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. A significant increase in <i>M.tb</i> growth was detected in the liver and spleen in DEM-treated <i>M.tb</i>-infected mice. Large, disorganized lymphocyte infiltrates were detected in the hepatic tissues of DEM-treated mice. Overall, GSH diminishment impaired the granulomatous response to <i>M.tb</i> in the liver and exacerbated <i>M.tb</i> growth in both the liver and spleen. These findings provide critical insights into the immunomodulatory role of GSH in TB pathogenesis and suggest potential therapeutic avenues for the treatment of extrapulmonary <i>M.tb</i> infections.