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

Proceedings of the National Academy of Sciences of the United States of America
Md Aejazur RahmanAdrie J C Steyn

Abstract

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, ther...Continue Reading

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Citations

Sep 3, 2020·Antibiotics·Álvaro MourenzaMichal Letek
Oct 20, 2020·Frontiers in Cellular and Infection Microbiology·Bridgette M CummingAdrie J C Steyn
Dec 18, 2020·Frontiers in Cellular and Infection Microbiology·Md Aejazur RahmanAdrie J C Steyn
Oct 27, 2020·Frontiers in Cellular and Infection Microbiology·Krishnaveni MohareerSharmistha Banerjee
Nov 14, 2020·Mucosal Immunology·Patricia P Ogger, Adam J Byrne
Mar 12, 2021·Antioxidants & Redox Signaling·Andre G BuretJohn L Wallace
Mar 23, 2021·Archives of Environmental & Occupational Health·Cristina M SantanaWilson K Rumbeiha
Mar 27, 2021·PLoS Pathogens·Georgios RenierisEvangelos J Giamarellos-Bourboulis
Aug 12, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Nahzli DilekCsaba Szabo
May 21, 2021·American Journal of Respiratory and Critical Care Medicine·Gordon WellsAdrie J C Steyn

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Datasets Mentioned

BETA
GSE143619

Methods Mentioned

BETA
genotyping
flow cytometry
RNA-seq

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