Department of Molecular Biology, Medical School, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
Center for Pediatric Clinical Studies, Children's Clinic, University of Tübingen, Hoppe-Seyler-Str. 1, D-72076 Tübingen, Germany.
Biol Chem. 2018 Sep 25;399(10):1203-1213. doi: 10.1515/hsz-2018-0161.
Pulmonary infections of cystic fibrosis (CF) patients with Staphylococcus aureus (S. aureus) occur very early in the disease. The molecular details that cause infection-susceptibility of CF patients to and mediate infection with S. aureus are poorly characterized. Therefore, we aimed to identify the role of α-toxin, a major S. aureus toxin, for pulmonary infection of CF mice. Infection with S. aureus JE2 resulted in severe pneumonia in CF mice, while wildtype mice were almost unaffected. Deficiency of α-toxin in JE2-Δhla reduced the pathogenicity of S. aureus in CF mice. However, CF mice were still more susceptible to the mutant S. aureus strain than wildtype mice. The S. aureus JE2 induced a marked increase of ceramide and a downregulation of sphingosine and acid ceramidase expression in bronchi of CF mice. Deletion of α-toxin reduced these changes after infection of CF mice. Similar changes were observed in wildtype mice, but at much lower levels. Our data indicate that expression of α-toxin is a major factor causing S. aureus infections in CF mice. Wildtype S. aureus induces a marked increase of ceramide and a reduction of sphingosine and acid ceramidase expression in bronchial epithelial cells of wildtype and CF mice, changes that determine infection susceptibility.
囊性纤维化（CF）患者的肺部感染金黄色葡萄球菌（S. aureus）发生在疾病的早期。导致 CF 患者易感染和介导金黄色葡萄球菌感染的分子细节特征尚未明确。因此，我们旨在确定α-毒素（金黄色葡萄球菌的一种主要毒素）在 CF 小鼠肺部感染中的作用。金黄色葡萄球菌 JE2 的感染导致 CF 小鼠发生严重肺炎，而野生型小鼠几乎未受影响。JE2-Δhla 中α-毒素的缺失降低了金黄色葡萄球菌在 CF 小鼠中的致病性。然而，CF 小鼠对突变的金黄色葡萄球菌菌株的易感性仍然高于野生型小鼠。金黄色葡萄球菌 JE2 在 CF 小鼠的支气管中诱导明显增加的神经酰胺，下调神经鞘氨醇和酸性神经酰胺酶的表达。感染 CF 小鼠后，缺失α-毒素可减少这些变化。在野生型小鼠中也观察到类似的变化，但水平要低得多。我们的数据表明，α-毒素的表达是导致 CF 小鼠金黄色葡萄球菌感染的主要因素。野生型金黄色葡萄球菌在野生型和 CF 小鼠的支气管上皮细胞中诱导明显增加神经酰胺和减少神经鞘氨醇和酸性神经酰胺酶的表达，这些变化决定了感染的易感性。
