Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection

被引:121
作者
Limoli, Dominique H. [1 ,2 ]
Whitfield, Gregory B. [3 ]
Kitao, Tomoe [4 ,5 ,6 ,7 ]
Ivey, Melissa L. [2 ,9 ]
Davis, Michael R., Jr. [8 ,10 ]
Grahl, Nora [1 ]
Hogan, Deborah A. [1 ]
Rahme, Laurence G. [4 ,5 ,6 ,7 ]
Howell, P. Lynne [3 ]
O'Toole, George A. [1 ]
Goldberg, Joanna B. [2 ,8 ]
机构
[1] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA
[2] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA
[3] Univ Toronto, Dept Biochem, Toronto, ON, Canada
[4] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA USA
[5] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[6] Harvard Med Sch, Boston, MA USA
[7] Shriners Hosp Children Boston, Boston, MA USA
[8] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22903 USA
[9] Ctr Dis Control & Prevent, Bacterial Special Pathogens Branch, Atlanta, GA USA
[10] Sweet Briar Coll, Dept Biol, Sweet Briar, VA 24595 USA
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院;
关键词
Pseudomonas aeruginosa; Staphylococcus aureus; biofilm; cystic fibrosis; mucoid; polymicrobial; C-DI-GMP; GENE-EXPRESSION; BIOFILM FORMATION; QUINOLONE SIGNAL; RHAMNOLIPIDS; RESISTANCE; POLYSACCHARIDE; COINFECTION; DIVERSITY; COCULTURE;
D O I
10.1128/mBio.00186-17
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 aeruginosa and Staphylococcus aureus are 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 that P. aeruginosa and/or S. aureus adopts phenotypes that allow coexistence during infection. We compared competitive interactions of P. aeruginosa and S. aureus isolates from mono-or coinfected CF patients employing in vitro coculture models. P. aeruginosa isolates from monoinfected patients were more competitive toward S. aureus than P. aeruginosa isolates from coinfected patients. We also observed that the least competitive P. aeruginosa isolates 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 kill S. aureus. Here, we show that production of alginate in mucoid strains is sufficient to inhibit anti-S. aureus activity 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 of S. aureus. These studies demonstrate alginate overproduction may be an important factor driving P. aeruginosa coinfection with S. aureus. IMPORTANCE Numerous 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 of P. aeruginosa is sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompete S. aureus, when the microbes are grown in coculture; thus we propose a mechanism whereby mucoid P. aeruginosa can coexist with S. aureus. Finally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens.
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页数:18
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