Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis

Significance Tuberculosis (TB) is responsible for millions of deaths each year and several billion people are latently infected with Mycobacterium tuberculosis (Mtb). Mtb modulates host factors, such as endogenous gaseous signalling molecules, to persist in humans for decades. H2S has diverse biological functions, including modulation of immunity and cellular respiration. However, the role of H2S in TB is unclear. We found that mice deficient in H2S production are more resistant to Mtb infection than WT mice. Upon infection, Mtb increases host H2S, which suppresses central carbon metabolism and increases inflammation. Distribution of H2S-producing enzymes in human TB lungs showed that H2S is produced at the site of infection. These findings identify glycolysis and H2S-producing enzymes as targets for TB host-directed therapies.
The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H2S in Mycobacterium tuberculosis (Mtb) pathogenesis. We showed that Mtb-infected CSE−/− mice survive longer than WT mice, and support reduced pathology and lower bacterial burdens in the lung, spleen, and liver. Similarly, in vitro Mtb infection of macrophages resulted in reduced colony forming units in CSE−/− cells. Chemical complementation of infected WT and CSE−/− macrophages using the slow H2S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H2S is the effector molecule regulating Mtb survival in macrophages. Furthermore, we demonstrate that CSE promotes an excessive innate immune response, suppresses the adaptive immune response, and reduces circulating IL-1β, IL-6, TNF-α, and IFN-γ levels in response to Mtb infection. Notably, Mtb infected CSE−/− macrophages show increased flux through glycolysis and the pentose phosphate pathway, thereby establishing a critical link between H2S and central metabolism. Our data suggest that excessive H2S produced by the infected WT mice reduce HIF-1α levels, thereby suppressing glycolysis and production of IL-1β, IL-6, and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S-producing enzymes in human necrotic, nonnecrotic, and cavitary pulmonary tuberculosis (TB) lesions. In summary, CSE exacerbates TB pathogenesis by altering immunometabolism in mice and inhibiting CSE or modulating glycolysis are potential targets for host-directed TB control.