Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, is one of the most severe diseases worldwide. The initial pulmonary localization of the pathogen often develops into systemic infection with high lethality. The present work investigated the role of sphingolipids, specifically the function of acid sphingomyelinase (Asm) and ceramide, in infection of murine macrophages in vitro and mice in vivo with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In vitro, we investigated macrophages from wild-type (wt) and Asm deficient (Asm−/−) mice to define signaling events induced by BCG infection and mediated by Asm. We demonstrate that infection of wt macrophages results in activation of Asm, which increases reactive oxygen species (ROS) via stimulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS promote BCG degradation by cathepsin D. Asm deficiency in macrophages abrogates these effects. In vivo studies reveal that wt mice rapidly control BCG infection, while Asm−/− mice fail to control the infection and kill the bacteria. Transplantation of wt macrophages into Asm−/− mice reversed their susceptibility to BCG, demonstrating the importance of Asm in macrophages for defense against BCG. These findings indicate that Asm is important for the control of BCG infection.
Highlights
Sphingomyelinases are enzymes classified according to the optimal pH for their activity: acid, neutral, or alkaline [1]
The results showed that ablation of cathepsin D (CTSD) expression led to a higher bacterial burden in wt macrophages but had no additional effect on acid sphingomyelinase (Asm)-deficient cells (Figure 3F), supporting our notion that CTSD is essential for killing Bacillus Calmette-Guérin (BCG) in macrophages, which is absent in Asm-deficient macrophages
(Asm)/ceramide system is important in the control of BCG infection (Figure 8)
Summary
Sphingomyelinases are enzymes classified according to the optimal pH for their activity: acid, neutral, or alkaline [1]. Acid sphingomyelinase and ceramide have been shown to be crucially involved in the host response to various bacteria, including pathogenic mycobacteria, several viruses, and some parasites [5,6,7,8,9,10,11,12,13,14]. Deficiency of acid sphingomyelinase often leads to increased susceptibility of the host to pathogens, such as Pseudomonas aeruginosa, Listeria monocytogenes, Salmonella typhimurium, and Staphylococcus aureus via distinct mechanisms including failure of internalization, loss of fusion of bacteria-containing phagosomes with lysosomes, or a defect in the nicotinamide adenine dinucleotide phosphate (NADPH)-mediated release of reactive oxygen species (ROS) [7,8,9,11,15]. Previous studies provide evidence for a specific interaction of acid-sphingomyelinase-derived ceramide with cathepsin D (CTSD), leading to enhanced enzymatic activity and proteolytic activation of proteins to be secreted [16]
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