Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa

Abstract

Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

Variability of the response of human vaginal Lactobacillus crispatus to 17β-estradiol

“…As an amphiphilic molecule, 17β-estradiol can integrate into membranes and destabilize their structure 18 . This phenomenon has been particularly observed in Gram-negative bacteria, such as Helicobacter pylori 18 and Pseudomonas aeruginosa 31 . In this regard, the absence of an effect of 17β-estradiol on the membrane integrity of L. crispatus V4 can be explained by the higher protection conferred by a complete outer S-layer envelope.…”

Effect of Phthalates and Their Substitutes on the Physiology of Pseudomonas aeruginosa

“…Noticeably, membrane fluidity alterations were shown to impact attachment and biofilm formation [78]. Sex steroids have been found to induce membrane stress responses in P. aeruginosa [79], and in some strains of Lactobacillus crispatus, exposure to 17β-estradiol led to increased membrane fluidity and adhesion to vaginal mucosa cells [40]. Similarly, P. aeruginosa that was infected by the filamentous phage Pf4, displayed increased membrane fluidity and biofilm formation [55].…”

Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents

“…However, an increased susceptibility of male C3HeB/FeJ mice has been reported in the oral aspiration pneumonia model ( Luna et al, 2019 ). In humans, women with cystic fibrosis and P. aeruginosa infection have worse outcomes than men ( Demko et al, 1995 ), which has been partly attributed to estrogen effects ( Vidaillac et al, 2020 ). In the case of K. pneumoniae infection, female mice have showed higher survival rates than males although exposure to ozone reversed the trend and resulted in female mice surviving less than males ( Mikerov et al, 2011 ).…”