PLX112438

GSE143619: Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognised to play a crucial role in human health. However, a role for host H2S in pathogenesis has not yet been demonstrated. Using cystathionine -lyase (CSE) deficient mice, we demonstrated an unexpected role of H2S in Mtb pathogenesis. We showed that Mtb-infected CSE-/- mice survive longer than wild-type 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 (CFUs) in CSE-/-cells. Chemical complementation of infected wild-type 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 IL1, IL-6, TNF, and IFN- 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 wild type mice reduce HIF-1 levels, thereby suppressing glycolysis and production of IL-1, IL-6 and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S producing enzymes in human necrotic, non-necrotic and cavitary pulmonary 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. SOURCE: Adrie,JC,Steyn (asteyn@uab.edu) - UAB