Severe impairment in early host defense against Listeria monocytogenes in mice deficient in acid sphingomyelinase.
The phagolysosomal compartment is crucial for the defense against infection with intracellular pathogens. Within this compartment, the TNF- and IFN-gamma-responsive acid sphingomyelinase (ASMase) generates the signaling molecule ceramide, resulting in the activation of proteases like cathepsin D. To investigate the possible role of ASMase as a mediator of the antibacterial effects of TNF and IFN-gamma, ASMase(-/-) mice were infected with Listeria monocytogenes. ASMase(-/-) mice showed a dramatically increased susceptibility to L. monocytogenes (LD(50) approximately 100 CFU) when compared with syngeneic wild-type mice (LD(50) approximately 10,000 CFU). In L. monocytogenes-challenged ASMase(-/-) mice, IFN-gamma serum levels as well as IL-1 beta and IL-6 secretion by macrophages were similar to those observed in wild-type C57BL/6 mice. Although macrophages and granulocytes from ASMase(-/-) mice showed intact production of reactive nitrogen intermediates and oxidative burst, ASMase(-/-) macrophages proved completely incapable of restricting the growth of L. monocytogenes in vitro. The results of this study suggest that ASMase is crucially required for the intracellular control of L. monocytogenes in macrophages and granulocytes by nonoxidative mechanisms.
Utermöhlen
Olaf
O
Institute for Medical Microbiology, Immunology and Hygiene, Medical Center of the University of Cologne, Cologne, Germany. olaf.utermoehlen@medizin.uni-koeln.de
Karow
Ulrike
U
Löhler
Jürgen
J
Krönke
Martin
M
D000818:Animals; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007928:Lethal Dose 50; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008099:Liver / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D010084:Oxidation-Reduction; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000235:genetics*
D013108:Sphingomyelin Phosphodiesterase