Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
mBio. 2020 Sep 29;11(5):e01774-20. doi: 10.1128/mBio.01774-20.
Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid 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 This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting persistence of the bacteria. The steroid-induced 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 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. Molecular mechanisms by which sex steroids interact with to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting 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 based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the 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 infection.
雌激素是一种主要的女性性激素，已被证明可促进慢性呼吸道疾病（包括囊性纤维化）患者气道中粘液的选择。这导致长期持续存在、临床结果较差和治疗选择有限。在这项研究中，我们证明了在生理浓度下，性激素（包括睾酮和雌三醇）会诱导 中的膜应激反应。这表现为毒力增加，继而引发炎症和释放促炎的外膜囊泡，促进细菌的持续存在。类固醇诱导的 反应与激素的分子极性和细菌的膜流变性特性相关。这种性激素与 之间相互作用的新机制解释了报道中囊性纤维化女性疾病严重程度增加的现象，并为调节性激素以实现对激素反应性菌株患者更好的临床结果提供了证据。性激素与 相互作用以调节其毒力的分子机制尚未报道。我们的工作首次描述了一种类固醇诱导的膜应激机制，该机制可促进 毒力，包括促炎的外膜囊泡的释放，从而导致炎症、宿主组织损伤和细菌清除减少。我们进一步证明，在纳摩尔（生理）浓度下，男性和女性性激素基于其动态膜流变性特性，促进临床株 的毒力。这项工作首次提供了对更好地理解和预测 对性激素的反应的机制见解，并解释了囊性纤维化等呼吸道疾病中观察到的个体间患者变异性，这些疾病因性别差异和慢性 感染而变得复杂。
