Abstract
BackgroundStaphylococcus aureus and Pseudomonas aeruginosa are often found together in the airways of cystic fibrosis (CF) patients. It was previously shown that the P. aeruginosa exoproduct 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) suppresses the growth of S. aureus and provokes the emergence of small-colony variants (SCVs). The presence of S. aureus SCVs as well as biofilms have both been associated with chronic infections in CF.ResultsWe demonstrated that HQNO stimulates S. aureus to form a biofilm in association with the formation of SCVs. The emergence of SCVs and biofilm production under HQNO exposure was shown to be dependent on the activity of the stress- and colonization-related alternative sigma factor B (SigB). Analysis of gene expression revealed that exposure of a prototypical S. aureus strain to HQNO activates SigB, which was leading to an increase in the expression of the fibronectin-binding protein A and the biofilm-associated sarA genes. Conversely, the quorum sensing accessory gene regulator (agr) system and the α-hemolysin gene were repressed by HQNO. Experiments using culture supernatants from P. aeruginosa PAO1 and a double chamber co-culture model confirmed that P. aeruginosa stimulates biofilm formation and activates SigB in a S. aureus strain isolated from a CF patient. Furthermore, the supernatant from P. aeruginosa mutants unable to produce HQNO induced the production of biofilms by S. aureus to a lesser extent than the wild-type strain only in a S. aureus SigB-functional background.ConclusionsThese results suggest that S. aureus responds to HQNO from P. aeruginosa by forming SCVs and biofilms through SigB activation, a phenomenon that may contribute to the establishment of chronic infections in CF patients.
Highlights
Staphylococcus aureus and Pseudomonas aeruginosa are often found together in the airways of cystic fibrosis (CF) patients
Using small-colony variants (SCVs) isolated from cystic fibrosis patients, we have previously demonstrated that the alternative transcription sigma factor B (SigB) influences the expression of several virulence factors and is associated with an increased ability to adhere, invade and persist within host cells [15,19]
HQNO inhibits the growth of normal strains and provokes the emergence of SCVs in S. aureus Fig. 1 confirms that HQNO suppresses the growth of S. aureus and causes the emergence of SCVs
Summary
Staphylococcus aureus and Pseudomonas aeruginosa are often found together in the airways of cystic fibrosis (CF) patients. The presence of S. aureus SCVs as well as biofilms have both been associated with chronic infections in CF. Cystic fibrosis (CF) is fundamentally a genetic disorder, the majority of patients with CF may succumb to respiratory failure subsequent to chronic bacterial infections [1]. Lungs of CF patients are often infected with Staphylococcus aureus and Haemophilus influenzae, but these organisms are usually outnumbered by Pseudomonas aeruginosa as patients become older. The biofilm lifestyle is recognized as an integrated and complex polymicrobial community and it is thought that cell-to-cell interspecies signals play a role in the control of this behavior [11]
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