Wheeler Kelsey M, Oh Myung Whan, Fusco Julianna, Mershon Aishlinn, Kim Erin, De Oliveira Antonia, Rahme Laurence G
Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.
bioRxiv. 2025 May 17:2025.05.16.654325. doi: 10.1101/2025.05.16.654325.
Infections often occur in complex niches consisting of multiple bacteria. Despite the in-creasing awareness, there is a fundamental gap in understanding which interactions govern mi-crobial community composition. Pseudomonas aeruginosa is frequently isolated from monomicrobi-al and polymicrobial human infections. This pathogen forms polymicrobial infections with other ESKAPEE pathogens and defies eradication by conventional therapies. By analyzing the competi-tion within cocultures of P. aeruginosa and representative secondary pathogens that commonly co-infect patients, we demonstrate the antagonism of P. aeruginosa against other ESKAPEE pathogens and the contribution of this pathogen's multiple quorum sensing (QS) systems in these interac-tions. QS is a highly conserved bacterial cell-to-cell communication mechanism that coordinates collective gene expressions at the population level, and it is also involved in P. aeruginosa virulence. Using a collection of P. aeruginosa QS mutants of the three major systems, LasR/LasI, MvfR/PqsABCDE, and RhlR/RhlI and mutants of several QS-regulated functions, we reveal that MvfR and, to a lesser extent, LasR and RhlR control competition between P. aeruginosa and other microbes, possibly through their positive impact on pyoverdine, pyochelin, and phenazine genes. We show that MvfR inhibition alters competitive interspecies interactions and preserves the coexistence of P. aeruginosa with ESKAPEE pathogens tested while disarming the pathogens' ability to form biofilm and adhere to lung epithelial cells. Our results highlight the role of MvfR inhibition in modulating microbial competitive interactions across multiple species, while simultaneously atten-uating virulence traits. These findings reveal the complexity and importance of QS in interspecies interactions and underscore the impact of the anti-virulence approach in microbial ecology and its importance for treating polymicrobial infections.
感染常常发生在由多种细菌组成的复杂生态位中。尽管人们的认识不断提高，但在理解哪些相互作用决定微生物群落组成方面仍存在根本性差距。铜绿假单胞菌经常从人类的单微生物和多微生物感染中分离出来。这种病原体与其他ESKAPEE病原体形成多微生物感染，并且常规疗法难以将其根除。通过分析铜绿假单胞菌与通常共同感染患者的代表性继发性病原体的共培养物中的竞争情况，我们证明了铜绿假单胞菌对其他ESKAPEE病原体的拮抗作用以及该病原体的多种群体感应（QS）系统在这些相互作用中的作用。群体感应是一种高度保守的细菌细胞间通讯机制，可在群体水平上协调集体基因表达，并且它也与铜绿假单胞菌的毒力有关。使用三大系统LasR/LasI、MvfR/PqsABCDE和RhlR/RhlI的一系列铜绿假单胞菌QS突变体以及几种QS调控功能的突变体，我们发现MvfR以及在较小程度上LasR和RhlR控制着铜绿假单胞菌与其他微生物之间的竞争，可能是通过它们对绿脓菌素、焦磷酸铁和吩嗪基因的积极影响。我们表明，抑制MvfR会改变种间竞争相互作用，并保持铜绿假单胞菌与所测试的ESKAPEE病原体共存，同时消除病原体形成生物膜和粘附于肺上皮细胞的能力。我们的结果突出了抑制MvfR在调节多种物种间微生物竞争相互作用中的作用，同时减弱毒力特征。这些发现揭示了群体感应在种间相互作用中的复杂性和重要性，并强调了抗毒力方法在微生物生态学中的影响及其对治疗多微生物感染的重要性。
