Pseudomonas aeruginosaAlginate Overproduction Promotes Coexistence withStaphylococcus aureusin a Model of Cystic Fibrosis Respiratory Infection.
While complex intra- and interspecies microbial community dynamics are apparent during chronic infections and likely alter patient health outcomes, our understanding of these interactions is currently limited. For example,Pseudomonas aeruginosaandStaphylococcus aureusare often found to coinfect the lungs of patients with cystic fibrosis (CF), yet these organisms compete under laboratory conditions. Recent observations that coinfection correlates with decreased health outcomes necessitate we develop a greater understanding of these interbacterial interactions. In this study, we tested the hypothesis thatP. aeruginosaand/orS. aureusadopts phenotypes that allow coexistence during infection. We compared competitive interactions ofP. aeruginosaandS. aureusisolates from mono- or coinfected CF patients employingin vitrococulture models.P. aeruginosaisolates from monoinfected patients were more competitive towardS. aureusthanP. aeruginosaisolates from coinfected patients. We also observed that the least competitiveP. aeruginosaisolates possessed a mucoid phenotype. Mucoidy occurs upon constitutive activation of the sigma factor AlgT/U, which regulates synthesis of the polysaccharide alginate and dozens of other secreted factors, including some previously described to killS. aureusHere, we show that production of alginate in mucoid strains is sufficient to inhibit anti-S. aureusactivity independent of activation of the AlgT regulon. Alginate reduces production of siderophores, 2-heptyl-4-hydroxyquinolone-N-oxide (HQNO), and rhamnolipids-each required for efficient killing ofS. aureusThese studies demonstrate alginate overproduction may be an important factor drivingP. aeruginosacoinfection withS. aureusIMPORTANCENumerous deep-sequencing studies have revealed the microbial communities present during respiratory infections in cystic fibrosis (CF) patients are diverse, complex, and dynamic. We now face the challenge of determining the influence of these community dynamics on patient health outcomes and identifying candidate targets to modulate these interactions. We make progress toward this goal by determining that the polysaccharide alginate produced by mucoid strains ofP. aeruginosais sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompeteS. aureus, when the microbes are grown in coculture; thus we propose a mechanism whereby mucoidP. aeruginosacan coexist withS. aureusFinally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens.
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.|Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Dominique H
DH
Limoli
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Gregory B
GB
Whitfield
Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts, USA.
Tomoe
T
Kitao
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Melissa L
ML
Ivey
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Michael R
MR
Davis
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Nora
N
Grahl
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Deborah A
DA
Hogan
Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts, USA.
Laurence G
LG
Rahme
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
P Lynne
PL
Howell
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA georgeo@dartmouth.edu joanna.goldberg@emory.edu.
George A
GA
O'Toole
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA georgeo@dartmouth.edu joanna.goldberg@emory.edu.|Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Joanna B
JB
Goldberg
D000464:Alginates / Q000378:metabolism*; D060085:Coinfection / Q000382:microbiology*; D003550:Cystic Fibrosis / Q000150:complications; D020723:Glucuronic Acid / Q000378:metabolism; D006603:Hexuronic Acids / Q000378:metabolism; D006801:Humans; D056265:Microbial Interactions; D008962:Models, Theoretical; D011552:Pseudomonas Infections / Q000150:complications* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000254:growth & development* / Q000378:metabolism; D012141:Respiratory Tract Infections; D013203:Staphylococcal Infections / Q000150:complications* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000254:growth & development*
D000464:Alginates; D006603:Hexuronic Acids; D020723:Glucuronic Acid
Pseudomonas aeruginosa; Staphylococcus aureus; biofilm; cystic fibrosis; mucoid; polymicrobial