期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 12, 页码 6663-6674出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1919211117
关键词
tuberculosis; H2S; hydrogen sulfide; pathogenesis; metabolism
资金
- NIH [R01Al111940, R01AI134810, R01AI137043, R61AI138280, R21A127182, T32HL13640]
- Bill and Melinda Gates Foundation Award [OPP1130017]
- University of Alabama at Birmingham Diabetes Research Center Bio-Analytics Redox Biology Core [P30DK079626]
- University of Alabama at Birmingham Center for AIDS Research
- University of Alabama at Birmingham Center for Free Radical Biology
- University of Alabama at Birmingham Infectious Diseases and Global Health and Vaccines Initiative
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2017-04392]
- US Civilian Research & Development Foundation (CRDF Global)
- South African Medical Research Council
- National Research Foundation of South Africa
The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine gamma-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-1 beta, IL-6, TNF-alpha, and IFN-gamma 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-1 alpha levels, thereby suppressing glycolysis and production of IL-1 beta, 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.
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