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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 <i>Staphylococcus aureus</i>, <i>Pseudomonas aeruginosa</i>, and nontuberculous mycobacteria, particularly <i>Mycobacterium abscessus</i>. Unfortunately, <i>M. abscessus</i> infections are increasing in prevalence and are associated with the rapid deterioration of CF patients. The treatment options for <i>M. abscessus</i> 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 <i>M. abscessus</i> infection, resulting in a higher incidence of infections in CF mice. Notably, treatment of <i>M. abscessus</i> 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 <i>M. abscessus</i> infections. Our findings demonstrate that pulmonary sphingosine levels are important in controlling <i>M. abscessus</i> infection. These results offer a promising therapeutic avenue for CF patients with pulmonary <i>M. abscessus</i> infections.