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Virulence. 2018;9(1):1008-1018. doi: 10.1080/21505594.2018.1489198.

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice.

Author information

1
a Department of Diagnostics and Public Health , University of Verona , Verona , Italy.
2
b Department of Computer Science , University of Verona , Verona , Italy.
3
c Department of Medicine , University of Verona , Verona , Italy.
4
d Cystic Fibrosis Center , Azienda Ospedaliera Universitaria Integrata di Verona , Verona , Italy.

Abstract

BACKGROUND:

Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathogens and defective immune system cooperate in developing a constant cycle of infection and inflammation. The major pathogen, Pseudomonas aeruginosa, secretes a multitude of virulence factors involved in host immune response and lung tissue damage. In this study, we examined the possible anti-inflammatory effects of molecules inhibiting P. aeruginosa virulence factors.

METHODS:

Pyocyanin, pyoverdine and proteases were measured in bacterial culture supernatant from different P. aeruginosa strains. Inhibition of virulence factors by sub-inhibitory concentrations of clarithromycin and by protease inhibitors was evaluated. Lung inflammatory response was monitored by in vivo bioluminescence imaging in wild-type and CFTR-knockout mice expressing a luciferase gene under the control of a bovine IL-8 promoter.

RESULTS:

The amount of proteases, pyocyanin and pyoverdine secreted by P. aeruginosa strains was reduced after growth in the presence of a sub-inhibitory dose of clarithromycin. Intratracheal challenge with culture supernatant containing bacteria-released products induced a strong IL-8-mediated response in mouse lungs while lack of virulence factors corresponded to a reduction in bioluminescence emission. Particularly, sole inactivation of proteases by inhibitors Ilomastat and Marimastat also resulted in decreased lung inflammation.

CONCLUSIONS:

Our data support the assumption that virulence factors are involved in P. aeruginosa pro-inflammatory action in CF lungs; particularly, proteases seem to play an important role. Inhibition of virulence factors production and activity resulted in decreased lung inflammation; thus, clarithromycin and protease inhibitors potentially represent additional therapeutic therapies for P. aeruginosa-infected patients.

KEYWORDS:

Cystic fibrosis; Pseudomonas aeruginosa; clarithromycin; in vivo imaging; lung inflammation; protease inhibitors; virulence factors

PMID:
29938577
PMCID:
PMC6086295
DOI:
10.1080/21505594.2018.1489198
[Indexed for MEDLINE]
Free PMC Article

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