Sex Steroids Induce Membrane Stress Responses and Virulence Properties in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
Celine Vidaillac,
Valerie Fei Lee Yong,
Marie-Stephanie Aschtgen,
Jing Qu,
Shuowei Yang,
Guangfu Xu,
Zi Jing Seng,
Alexandra C. Brown,
Md Khadem Ali,
Tavleen K. Jaggi,
Jagadish Sankaran,
Yong Hwee Foo,
Francesco Righetti,
Anu Maashaa Nedumaran,
Micheál Mac Aogáin,
Dan Roizman,
Jean-Alexandre Richard,
Thomas R. Rogers,
Masanori Toyofuku,
Dahai Luo,
Edmund Loh,
Thorsten Wohland,
Bertrand Czarny,
Jay C. Horvat,
Philip M. Hansbro,
Liang Yang,
Liang Li,
Staffan Normark,
Birgitta Henriques-Normark,
Sanjay H. Chotirmall
Affiliations
Celine Vidaillac
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Valerie Fei Lee Yong
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Marie-Stephanie Aschtgen
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Jing Qu
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
Shuowei Yang
Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
Guangfu Xu
Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
Zi Jing Seng
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
Alexandra C. Brown
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
Md Khadem Ali
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
Tavleen K. Jaggi
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Jagadish Sankaran
Department of Biological Sciences, National University of Singapore, Singapore
Yong Hwee Foo
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
Francesco Righetti
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
Anu Maashaa Nedumaran
School of Materials Science and Engineering (MSE), Nanyang Technological University, Singapore
Micheál Mac Aogáin
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Dan Roizman
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
Jean-Alexandre Richard
Functional Molecules and Polymers, Institute of Chemical and Engineering Sciences, ICES, Agency for Science, Technology, and Research, A*STAR, Singapore
Thomas R. Rogers
Department of Clinical Microbiology, Trinity College Dublin, St. James’s Hospital Campus, Dublin, Ireland
Masanori Toyofuku
Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
Dahai Luo
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Edmund Loh
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
Thorsten Wohland
Department of Biological Sciences, National University of Singapore, Singapore
Bertrand Czarny
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Jay C. Horvat
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
Philip M. Hansbro
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
Liang Yang
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
Liang Li
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
Staffan Normark
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Birgitta Henriques-Normark
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Sanjay H. Chotirmall
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
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.
