IMR Press / FBE / Volume 8 / Issue 2 / DOI: 10.2741/E769

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article

Inhibition of neutral sphingomyelinase protects mice against systemic tuberculosis

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1 Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
2 Institute of Nutritional Science, Faculty of Mathematics and Natural Science, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany
3 Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
4 School of Immunity and Infection, Institute of Biomedical Research, The Medical School, Edgbaston, University of Birmingham, United Kingdom
5 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA

*Author to whom correspondence should be addressed.

Academic Editor: Pin-Lan Li

Front. Biosci. (Elite Ed) 2016, 8(2), 311–325; https://doi.org/10.2741/E769
Published: 1 January 2016
(This article belongs to the Special Issue Molecular pathobiology of lipid mediators)
Abstract

Tuberculosis is one of the most serious infectious diseases worldwide. The initial pulmonal localization of the pathogens often develops into systemic infection with high lethality. We investigated the role of the mammalian neutral sphingomyelinase (Nsm)/ceramide system in systemic infection of mice and murine macrophages with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Our results demonstrate that BCG infection of RAW cells, a macrophage cell line, results in rapid activation of Nsm but not of acid sphingomyelinase (Asm). Activation of Nsm is associated with a massive release of superoxide. Genetic knock-down of Nsm in RAW cells prevented superoxide production upon BCG infection. Superoxide suppressed autophagy in BCG-infected macrophages in vitro and in vivo: Knock-down of Nsm or inhibition of superoxide restored autophagy in macrophages and increased killing of intracellular bacteria upon BCG infection. Most importantly, autophagy was also massively increased in Nsm-heterozygous mice, protecting these mice from systemic BCG infections, granuloma development, and chronic infections of liver and spleen. These findings indicate that the Nsm/ceramide system plays a role in protecting mice against systemic tuberculosis by preventing superoxide-mediated inhibition of autophagy.

Keywords
Neutral Sphingomyelinase
Ceramide
Mycobacterium Bovis
Bacillus Calmette Guerin
BCG
Tuberculosis
Superoxide
Autophagy
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