Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Cell Rep. 2023 Mar 28;42(3):112270. doi: 10.1016/j.celrep.2023.112270. Epub 2023 Mar 16.
The cystic fibrosis (CF) respiratory tract harbors pathogenic bacteria that cause life-threatening chronic infections. Of these, Pseudomonas aeruginosa becomes increasingly dominant with age and is associated with worsening lung function and declining microbial diversity. We aimed to understand why P. aeruginosa dominates over other pathogens to cause worsening disease. Here, we show that P. aeruginosa responds to dynamic changes in iron concentration, often associated with viral infection and pulmonary exacerbations, to become more competitive via expression of the TseT toxic effector. However, this behavior can be therapeutically targeted using the iron chelator deferiprone to block TseT expression and competition. Overall, we find that iron concentration and TseT expression significantly correlate with microbial diversity in the respiratory tract of people with CF. These findings improve our understanding of how P. aeruginosa becomes increasingly dominant with age in people with CF and provide a therapeutically targetable pathway to help prevent this shift.
囊性纤维化（CF）呼吸道中存在导致危及生命的慢性感染的致病性细菌。其中，铜绿假单胞菌随着年龄的增长变得越来越占优势，与肺功能恶化和微生物多样性下降有关。我们旨在了解为什么铜绿假单胞菌比其他病原体更具优势，导致疾病恶化。在这里，我们表明铜绿假单胞菌对铁浓度的动态变化做出反应，铁浓度通常与病毒感染和肺部恶化有关，通过表达 TseT 毒性效应物变得更具竞争力。然而，这种行为可以使用铁螯合剂地拉罗司来靶向治疗，以阻断 TseT 的表达和竞争。总的来说，我们发现铁浓度和 TseT 的表达与 CF 患者呼吸道中的微生物多样性显著相关。这些发现提高了我们对 CF 患者中铜绿假单胞菌随年龄增长变得越来越占优势的理解，并提供了一种可治疗的靶向途径，以帮助预防这种转变。
