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 (LD50 similar to100 CFU) when compared with syngeneic wild-type mice (LD50 similar to10,000 CFU). In L. monocytogenes-challenged ASMase(-/-) mice, IFN-gamma serum levels as well as IL-1beta 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.