title: Inhibition of neutral sphingomyelinase protects mice against systemic tuberculosis.
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-Guerin (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.
authors.forename: Cao
authors.initials: C
authors.lastname: Li
authors.forename: Huiming
authors.initials: H
authors.lastname: Peng
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.forename: Aaron
authors.initials: A
authors.lastname: Seitz
authors.forename: Andrea
authors.initials: A
authors.lastname: Riehle
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilker
authors.forename: Matthias
authors.initials: M
authors.lastname: Soddemann
authors.forename: Burkard
authors.initials: B
authors.lastname: Kleuser
authors.forename: Michael
authors.initials: M
authors.lastname: Edwards
authors.forename: David
authors.initials: D
authors.lastname: Lammas
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany, heike.gulbins@uni-due.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Grassme
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004789:Enzyme Activation; D051379:Mice; D009163:Mycobacterium bovis / Q000472:pathogenicity; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D013481:Superoxides; D013108:Sphingomyelin Phosphodiesterase