Corticosteroids modulate biofilm formation and virulence of Pseudomonas aeruginosa

Corticosteroids are anti-inflammatory drugs commonly administered to patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis and similar lung pathologies, in which persistent infections with Pseudomonas aeruginosa are frequent. However, their therapeutic value is debatable because of their adverse impact on host immunity. The aim of this work was to determine the impact of budesonide and fluticasone propionate on P. aeruginosa biology. We found that these corticosteroids attenuated its intrinsic pro-inflammatory properties (reduction of IL-8 release compared to controls ca. 15 % (budesonide) and 50 % (fluticasone propionate)) and cellular invasiveness (25 % and 40 % respectively). Corticosteroids enhanced P. aeruginosa biofilm formation in a time/dose-dependent manner (around 1.6-fold for the highest concentration, with this increase occurring more readily in sputum media)) and stimulated the release of extracellular DNA (2-fold increase), a key component of the biofilm matrix. Regarding the mechanisms involved, our results suggest that corticosteroids diffuse through P. aeruginosa's membrane influencing its fluidity and triggering cell envelope stress signalling pathways, as shown by an initial increase in mucA (sigma 22 regulon) expression, outer membrane vesicle release and accumulation of cyclic diguanylate (c-di-GMP). Changes in the levels of this intracellular signalling molecule, responsible for the switch from planktonic to biofilm lifestyle, may explain some of the phenotypes observed. In conclusion, our data, first obtained with type strains and proved to be reproducible when using COPD clinical isolates, suggest that corticosteroids could mediate a faster acquisition of the phenotypic characteristics associated with P. aeruginosa long-term adaptation to the chronic lung niche without undergoing mutation.