Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by the deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) and often leads to pulmonary infections caused by various pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and nontuberculous mycobacteria, particularly Mycobacterium abscessus. Unfortunately, M. abscessus infections are increasing in prevalence and are associated with the rapid deterioration of CF patients. The treatment options for M. abscessus infections are limited, requiring the urgent need to comprehend infectious pathogenesis and develop new therapeutic interventions targeting affected CF patients. Here, we show that the deficiency of CFTR reduces sphingosine levels in bronchial and alveolar epithelial cells and macrophages from CF mice and humans. Decreased sphingosine contributes to the susceptibility of CF tissues to M. abscessus infection, resulting in a higher incidence of infections in CF mice. Notably, treatment of M. abscessus with sphingosine demonstrated potent bactericidal activity against the pathogen. Most importantly, restoration of sphingosine levels in CF cells, whether human or mouse, and in the lungs of CF mice, provided protection against M. abscessus infections. Our findings demonstrate that pulmonary sphingosine levels are important in controlling M. abscessus infection. These results offer a promising therapeutic avenue for CF patients with pulmonary M. abscessus infections.