Abstract
Cystic fibrosis (CF) is associated with chronic bacterial airway infections leading to lung insufficiency and decreased life expectancy. Staphylococcus aureus is one of the most prevalent pathogens isolated from the airways of CF patients. Mucoid colony morphology has been described for Pseudomonas aeruginosa, the most common pathogen in CF, but not for S. aureus. From the airways of 8 of 313 CF patients (2.5%) mucoid S. aureus isolates (n = 115) were cultured with a mean persistence of 29 months (range 1 month, 126 months). In contrast to non-mucoid S. aureus, mucoid isolates were strong biofilm formers. The upstream region of the ica operon, which encodes the proteins responsible for the synthesis of the polysaccharide intercellular adhesin (PIA), of mucoid isolates was sequenced. Spa-types of mucoid and non-mucoid strains were identical, but differed between patients. Mucoid isolates carried a 5 bp deletion in the intergenic region between icaR and icaA. During long-term persistence, from two patients subsequent non-mucoid isolates (n = 12) with 5 bp deletions were cultured, which did not produce biofilm. Sequencing of the entire ica operon identified compensatory mutations in various ica-genes including icaA (n = 7), icaD (n = 3) and icaC (n = 2). Six sequential isolates of each of these two patients with non-mucoid and mucoid phenotypes were subjected to whole genome sequencing revealing a very close relationship of the individual patient’s isolates. Transformation of strains with vectors expressing the respective wild-type genes restored mucoidy. In contrast to the non-mucoid phenotype, mucoid strains were protected against neutrophilic killing and survived better under starvation conditions. In conclusion, the special conditions present in CF airways seem to facilitate ongoing mutations in the ica operon during S. aureus persistence.
Highlights
Cystic fibrosis (CF) is one of the most common hereditary diseases in the Caucasian population caused by mutations of an important chloride channel and affects worldwide approximately 70,000 people [1]
Staphylococcus aureus is one of the most common pathogens isolated from the airways of cystic fibrosis (CF) patients
We identified unusual mucoid S. aureus isolates in 8 of 313 (2.5%) CF patients
Summary
Cystic fibrosis (CF) is one of the most common hereditary diseases in the Caucasian population caused by mutations of an important chloride channel (cystic fibrosis transmembrane regulator) and affects worldwide approximately 70,000 people [1]. Staphylococcus aureus is one of the first and today the most frequent isolated pathogen, which can be recovered from the airways of CF patients with increasing prevalence rates most likely due to early eradication strategies directed against Pseudomonas aeruginosa, which was the leading pathogen in CF for decades and which has been shown to be responsible for lung function decline [1,3]. Mucoid isolates of P. aeruginosa occur in late stages of CF after the patients experienced long-term persistence of non-mucoid P. aeruginosa phenotypes [4]. The recovery of mucoid isolates has been shown to play a greater role in lung disease progression than the recovery of non-mucoid P. aeruginosa isolates [4]. The underlying mechanism for mucoidy is caused by overproduction of alginate due to a mutation in the mucA gene [5,6]
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