Abstract
Polysaccharide intercellular adhesin (PIA), also known as poly-N-acetyl-β-(1–6)-glucosamine (PIA/PNAG) is an important component of Staphylococcus aureus biofilms and also contributes to resistance to phagocytosis. The proteins IcaA, IcaD, IcaB, and IcaC are encoded within the intercellular adhesin (ica) operon and synthesize PIA/PNAG. We discovered a mechanism of phase variation in PIA/PNAG expression that appears to involve slipped-strand mispairing. The process is reversible and RecA-independent, and involves the expansion and contraction of a simple tetranucleotide tandem repeat within icaC. Inactivation of IcaC results in a PIA/PNAG-negative phenotype. A PIA/PNAG-hyperproducing strain gained a fitness advantage in vitro following the icaC mutation and loss of PIA/PNAG production. The mutation was also detected in two clinical isolates, suggesting that under certain conditions, loss of PIA/PNAG production may be advantageous during infection. There was also a survival advantage for an icaC-negative strain harboring intact icaADB genes relative to an isogenic icaADBC deletion mutant. Together, these results suggest that inactivation of icaC is a mode of phase variation for PIA/PNAG expression, that high-level production of PIA/PNAG carries a fitness cost, and that icaADB may contribute to bacterial fitness, by an unknown mechanism, in the absence of an intact icaC gene and PIA/PNAG production.
Highlights
Phase variation functions as a reversible on/off switch for the expression of a particular gene
We found that MN8m cultures frequently exhibited an appearance that was somewhere between that of a turbid, non-mucoid strain and an autoaggregative mucoid strain (Fig. 1A). When these cultures were plated on Congo red agar (CRA), both mucoid colonies, which appear dry with irregular edges, and non-mucoid colonies, which are slick, circular, and occasionally surrounded by a transparent red perimeter, were observed (Fig. 1B)
The polysaccharide Polysaccharide intercellular adhesin (PIA)/polymer of b-1-6-linked N-acetylglucosamine (PNAG) plays an important role in virulence both through its contribution to biofilm formation and immune evasion
Summary
Phase variation functions as a reversible on/off switch for the expression of a particular gene. Slipped-strand mispairing is one mechanism that can lead to the production of a phase variant. Slipped-strand mispairing occurs during DNA replication when there is mispairing between mother and daughter DNA strands in regions of DNA that contain simple 1–10 nucleotide repeats [1]. This results in the addition or subtraction of one or more repeats that can bring about a change in transcriptional efficiency or shift the reading frame to alter or halt translation. Biofilm formation plays an important role, in device-related infections, and it contributes to antibiotic failure and resistance of the bacteria to host immune defenses
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