Lack of Sphingosine Causes Susceptibility to Pulmonary Staphylococcus Aureus Infections in Cystic Fibrosis

Abstract

Background: Pulmonary Staphylococcus aureus (S. aureus) infections occur early in a high percentage of cystic fibrosis (CF) patients and it is believed that these infections facilitate further colonization of CF lungs with Pseudomonas aeruginosa (P. aeruginosa). Previous studies demonstrated a marked reduction of sphingosine in tracheal and bronchial epithelial cells in CF compared to wild type mice, while ceramide is massively increased in CF mice. Methods: We investigated the effect of C18-sphingosine and C16-ceramide on S. aureus in vitro. Based on our results we performed pulmonary infections with S. aureus and tested the influence of sphingosine inhalation. Results: In vitro incubation of S. aureus with C18-sphingosine rapidly killed S. aureus, while C16-ceramide did not affect bacterial survival, but abrogated the effect of C18-sphingosine when applied together. The in vivo infection experiments revealed a high susceptibility of CF mice to pulmonary infection with S. aureus. Inhalation of C18-sphingosine rescued CF mice from pulmonary infections with different clinical S. aureus isolates, including a methicillin-resistant S. aureus (MRSA) strain. Conclusions: Our data indicate that the imbalance between ceramide and sphingosine in the CF respiratory tract prevents killing of S. aureus and causes the high susceptibility of CF mice to pulmonary S. aureus infections.

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

“…It has been shown that sphingosine levels are reduced in epithelial cells of the airways of CF mice and that sphingosine kills P. aeruginosa and S. aureus, but also other pathogens, in vitro and in vivo [17,37]. Since levels of GlcCer are also reduced in CF, we hypothesised that GlcCer may also act bactericidal in vitro and that a combination of GlcCer and sphingosine may synergistically inhibit P. aeruginosa growth.…”

“…While the effects of ceramide and sphingosine in P. aeruginosa infections in cystic fibrosis have been well demonstrated [8,14,17,37], little is known about an effect of glycosphingolipids. Here, we demonstrate that levels of GlcCer are lower on the apical surface of tracheal and bronchial epithelial cells of CF mice than in WT mice.…”

“…Given that ceramide also plays a very critical role in cystic fibrosis and normalization of ceramide levels by blockers of the acid sphingomyelinase has been shown to prevent infection and inflammation in cystic fibrosis patients [42][43][44], we hypothesize that a therapy that combines normalization of ceramide levels with inhalation of glucosylceramide and/ or sphingosine [17,37] might be the most promising way preventing or treating existing bacterial infection in CF patients in the future. Since other drugs, like antibiotics, can also be applied via an inhalation therapy in CF [45], this way of application offers the benefits of a local administration with minimal adverse systemic effects.…”

“…Numerous studies have shown that expression of ceramide and sphingosine is altered in the respiratory tract of cystic fibrosis patients and mice and that both sphingolipids have an important role in P. aeruginosa infections [8,14,17,37]. Based on these findings, we aimed to determine if there is a difference in expression of the glycosphingolipids glucosylceramide (GlcCer) and lactosylceramide (LacCer) in the respiratory tract between wild type (WT) and CF mice.…”

Shufeng Jiedu Capsules Alleviate Lipopolysaccharide-Induced Acute Lung Inflammatory Injury via Activation of GPR18 by Verbenalin

“…ALRTI is generally more serious than an AURTI and is the most common reason for outpatient physician office visits. Moreover, ALRTIs are the leading cause of death among all infectious diseases [1][2][3]. ALRTIs are generally treated with antibiotics, and approximately 41% of all adult ambulatory antibiotics prescriptions are for respiratory infections [4,5].…”