Abstract
ABSTRACTPseudomonas aeruginosa causes chronic pulmonary infections in patients with cystic fibrosis (CF). P. aeruginosa mucoid conversion, defined by overproduction of the exopolysaccharide alginate, correlates with accelerated decline in CF patient lung function. Recalcitrance of the mucoid phenotype to clearance by antibiotics and the immune response is well documented. However, despite advantages conferred by mucoidy, mucoid variants often revert to a nonmucoid phenotype both in vitro and in vivo. Mixed populations of mucoid isolates and nonmucoid revertants are recovered from CF lungs, suggesting a selective benefit for coexistence of these variants. In this study, cocultures of mucoid and nonmucoid variants exhibited enhanced resistance to two host antimicrobials: LL-37, a cationic antimicrobial peptide, and hydrogen peroxide (H2O2). Alginate production by mucoid isolates protected nonmucoid variants in consortia from LL-37, as addition of alginate exogenously to nonmucoid variants abrogated LL-37 killing. Conversely, nonmucoid revertants shielded mucoid variants from H2O2 stress via catalase (KatA) production, which was transcriptionally repressed by AlgT and AlgR, central regulators of alginate biosynthesis. Furthermore, extracellular release of KatA by nonmucoid revertants was dependent on lys, encoding an endolysin implicated in autolysis and extracellular DNA (eDNA) release. Overall, these data provide a rationale to study interactions of P. aeruginosa mucoid and nonmucoid variants as contributors to evasion of innate immunity and persistence within the CF lung.
Highlights
Pseudomonas aeruginosa causes chronic pulmonary infections in patients with cystic fibrosis (CF)
Mixed Variants of P. aeruginosa Evade Immune Effectors mucoid and nonmucoid P. aeruginosa populations in evading host effectors, we focused on two innate antimicrobials found within the CF lung: LL-37 and H2O2 [7,8,9]
The mucoid strain, FRD1, was significantly more resistant to LL-37 than the nonmucoid strain, FRD1 algD, as previously reported [12]; in coculture, the susceptibilities of both strains to LL-37 were similar, suggesting that FRD1 algD was partially rescued from LL-37 by FRD1 (Fig. 1A)
Summary
Pseudomonas aeruginosa causes chronic pulmonary infections in patients with cystic fibrosis (CF). Nonmucoid revertants shielded mucoid variants from H2O2 stress via catalase (KatA) production, which was transcriptionally repressed by AlgT and AlgR, central regulators of alginate biosynthesis. Extracellular release of KatA by nonmucoid revertants was dependent on lys, encoding an endolysin implicated in autolysis and extracellular DNA (eDNA) release Overall, these data provide a rationale to study interactions of P. aeruginosa mucoid and nonmucoid variants as contributors to evasion of innate immunity and persistence within the CF lung. We show that mixed-variant communities of P. aeruginosa demonstrate advantages in evasion of innate antimicrobials via production of shared goods: alginate and catalase These data argue for therapeutically targeting multiple constituents (both mucoid and nonmucoid variants) within diversified P. aeruginosa communities in vivo, as these variants can differentially shield one another from components of the host response. Though AlgT is critical for mucoid conversion, the AlgT regulon is predicted to consist of 293 open reading frames, indicating a broad role in P. aeruginosa gene regulation [21, 22]
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