Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis
Md. Aejazur Rahman, Bridgette M. Cumming, Kelvin W. Addicott, Hayden T. Pacl, Shannon Russell, Kievershen Nargan, Threnesan Naidoo, Pratistadevi K. Ramdial, John Adamson, Rui Wang, Adrie J. C. Steyn
Abstract
The ubiquitous gasotransmitter hydrogen sulfide (H 2 S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H 2 S 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 H 2 S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H 2 S 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 H 2 S and central metabolism. Our data suggest that excessive H 2 S 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 H 2 S-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.