Conditions associated with the cystic fibrosis defect promote chronic Pseudomonas aeruginosa infection.
BACKGROUND
Progress has been made in understanding how the cystic fibrosis (CF) basic defect produces lung infection susceptibility. However, it remains unclear why CF exclusively leads to chronic infections that are noninvasive and highly resistant to eradication. Although biofilm formation has been suggested as a mechanism, recent work raises questions about the role of biofilms in CF.


OBJECTIVE
To learn how airway conditions attributed to CF transmembrane regulator dysfunction could lead to chronic infection, and to determine if biofilm-inhibiting genetic adaptations that are common in CF isolates affect the capacity of Pseudomonas aeruginosa to develop chronic infection phenotypes.


METHODS
We studied P. aeruginosa isolates grown in agar and mucus gels containing sputum from patients with CF and measured their susceptibility to killing by antibiotics and host defenses. We also measured the invasive virulence of P. aeruginosa grown in sputum gels using airway epithelial cells and a murine infection model.


RESULTS
We found that conditions likely to result from increased mucus density, hyperinflammation, and defective bacterial killing could all cause P. aeruginosa to grow in bacterial aggregates. Aggregated growth markedly increased the resistance of bacteria to killing by host defenses and antibiotics, and reduced their invasiveness. In addition, we found that biofilm-inhibiting mutations do not impede aggregate formation in gel growth environments.


CONCLUSIONS
Our findings suggest that conditions associated with several CF pathogenesis hypotheses could cause the noninvasive and resistant infection phenotype, independently of the bacterial functions needed for biofilm formation.
1 Department of Medicine, and.
Benjamin J
BJ
Staudinger
Jocelyn Fraga
JF
Muller
Skarphéðinn
S
Halldórsson
Blaise
B
Boles
Angus
A
Angermeyer
Dao
D
Nguyen
Henry
H
Rosen
Olafur
O
Baldursson
Magnús
M
Gottfreðsson
Guðmundur Hrafn
GH
Guðmundsson
Pradeep K
PK
Singh
D000818:Animals; D018441:Biofilms; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics / Q000382:microbiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005819:Genetic Markers; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D011552:Pseudomonas Infections / Q000209:etiology* / Q000235:genetics / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology; D013183:Sputum / Q000378:metabolism / Q000382:microbiology; D014774:Virulence
D015415:Biomarkers; D005819:Genetic Markers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019272:Leukocyte Elastase