Schwyter Lukas, Niggli Selina, Zajac Natalia, Poveda Lucy, Wolski Witold Eryk, Panse Christian, Schlapbach Ralph, Kümmerli Rolf, Grossmann Jonas
Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland.
mSystems. 2025 Jul 31:e0026225. doi: 10.1128/msystems.00262-25.
and frequently co-occur in infections, and there is evidence that their interactions can negatively affect disease outcomes. is known to be dominant, often compromising through the secretion of inhibitory compounds. We previously demonstrated that can become resistant to growth-inhibitory compounds during experimental evolution. While resistance arose rapidly, the underlying mechanisms were not obvious as only a few genetic mutations were associated with resistance, while ample phenotypic changes occurred. We thus hypothesize that resistance may result from a combination of phenotypic responses and genetic adaptation. Here, we tested this hypothesis using proteomics. We first focused on an evolved strain that acquired a single mutation in (encoding a transmembrane transporter unit) upon exposure to supernatant. We show that this mutation leads to a complete abolishment of transporter synthesis, which confers moderate protection against quinolone signal and selenocystine, two toxic compounds produced by . However, this genetic effect was minor compared to the fundamental phenotypic changes observed at the proteome level when both ancestral and evolved strains were exposed to supernatant. Major changes involved the downregulation of virulence factors, metabolic pathways, and membrane transporters, and the upregulation of reactive oxygen species scavengers and an efflux pump. Our results suggest that the observed multivariate phenotypic response is a powerful adaptive strategy, offering instant protection against competitors in fluctuating environments and reducing the need for hard-wired genetic adaptations.IMPORTANCEDifferent bacterial pathogens can co-occur in infections, where they interact with one another and influence disease severity. Previous research showed that pathogens can evolve and adapt to co-infecting species. Here, we show that evolution through genetic mutations and selection is not necessarily required to change pathogen behavior. Instead, we found that the human pathogen is able to plastically respond to the presence of , a competing pathogen. Through proteomics and metabolomics, we demonstrate that undergoes substantial proteomic alterations in response to by downregulating virulence factor expression, changing metabolism, and mounting protective measures against toxic compounds. Our work highlights that pathogens possess sophisticated mechanisms to respond to competitors to secure growth and survival in polymicrobial infections. We predict such plastic responses to have significant impacts on infection outcomes.
它们在感染中经常共同出现，并且有证据表明它们之间的相互作用会对疾病结果产生负面影响。已知[细菌名称1]占主导地位，常常通过分泌抑制性化合物来抑制[细菌名称2]。我们之前证明，在实验进化过程中，[细菌名称2]能够对生长抑制性化合物产生抗性。虽然抗性迅速出现，但其潜在机制并不明显，因为只有少数基因突变与抗性相关，而同时发生了大量的表型变化。因此，我们假设抗性可能是表型反应和遗传适应共同作用的结果。在这里，我们使用蛋白质组学来验证这一假设。我们首先聚焦于一个经过进化的菌株，该菌株在暴露于[细菌名称1]的上清液后，在[基因名称]（编码一个跨膜转运蛋白单元）中获得了一个单一突变。我们表明，这个突变导致转运蛋白合成完全停止，这赋予了对[细菌名称1]产生的喹诺酮信号和硒代胱氨酸这两种有毒化合物的适度保护。然而，与当原始菌株和进化后的[细菌名称2]菌株都暴露于[细菌名称1]的上清液时在蛋白质组水平观察到的基本表型变化相比，这种遗传效应较小。主要变化包括毒力因子、代谢途径和膜转运蛋白的下调，以及活性氧清除剂和一个外排泵的上调。我们的结果表明，观察到的多变量表型反应是一种强大的适应性策略，在波动的环境中为抵御竞争者提供即时保护，并减少对固定遗传适应的需求。
重要性
不同的细菌病原体可在感染中共存，它们相互作用并影响疾病严重程度。先前的研究表明，病原体能够进化并适应共同感染的物种。在这里，我们表明，改变病原体行为不一定需要通过基因突变和选择来进化。相反，我们发现人类病原体[细菌名称2]能够灵活地应对竞争病原体[细菌名称1]的存在。通过蛋白质组学和代谢组学，我们证明[细菌名称2]通过下调毒力因子表达、改变代谢以及对有毒化合物采取保护措施，对[细菌名称1]的存在做出了大量蛋白质组学改变。我们的工作强调，病原体拥有复杂的机制来应对竞争者，以确保在多微生物感染中生长和存活。我们预测这种灵活反应会对感染结果产生重大影响。
