Khademi S M Hossein, Gabrielaite Migle, Paulsson Magnus, Knulst Mattis, Touriki Eleni, Marvig Rasmus L, Påhlman Lisa I
Department of Clinical Sciences Lund, Division of Infection Medicine, Lund University, Lund, Sweden.
Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark.
mSystems. 2021 Jun 29;6(3):e0052321. doi: 10.1128/mSystems.00523-21.
Bacterial pathogens evolve during chronic colonization of the human host by selection for pathoadaptive mutations. One of the emerging and understudied bacterial species causing chronic airway infections in patients with cystic fibrosis (CF) is Achromobacter xylosoxidans. It can establish chronic infections in patients with CF, but the genetic and phenotypic changes associated with adaptation during these infections are not completely understood. In this study, we analyzed the whole-genome sequences of 55 clinical A. xylosoxidans isolates longitudinally collected from the sputum of 6 patients with CF. Four genes encoding regulatory proteins and two intergenic regions showed convergent evolution, likely driven by positive selection for pathoadaptive mutations, across the different clones of A. xylosoxidans. Most of the evolved isolates had lower swimming motility and were resistant to multiple classes of antibiotics, while fewer of the evolved isolates had slower growth or higher biofilm production than the first isolates. Using a genome-wide association study method, we identified several putative genetic determinants of biofilm formation, motility and β-lactam resistance in this pathogen. With respect to antibiotic resistance, we discovered that a combination of mutations in pathoadaptive genes ( and ) and two other genes encoding regulatory proteins ( and ) were associated with increased resistance to meropenem and ceftazidime. Altogether, our results suggest that genetic changes within regulatory loci facilitate within-host adaptation of A. xylosoxidans and the emergence of adaptive phenotypes, such as antibiotic resistance or biofilm formation. A thorough understanding of bacterial pathogen adaptation is essential for the treatment of chronic bacterial infections. One unique challenge in the analysis and interpretation of genomics data is identifying the functional impact of mutations accumulated in the bacterial genome during colonization in the human host. Here, we investigated the genomic and phenotypic evolution of A. xylosoxidans in chronic airway infections of patients with CF and identified several mutations associated with the phenotypic evolution of this pathogen using genome-wide associations. Identification of phenotypes under positive selection and the associated mutations can enlighten the adaptive processes of this emerging pathogen in human infections and pave the way for novel therapeutic interventions.
细菌病原体在人类宿主的慢性定植过程中，通过选择致病适应性突变而发生进化。木糖氧化无色杆菌是一种在囊性纤维化（CF）患者中引发慢性气道感染且正在出现但研究不足的细菌物种。它可在CF患者中建立慢性感染，但这些感染期间与适应性相关的遗传和表型变化尚未完全明了。在本研究中，我们分析了从6例CF患者痰液中纵向收集的55株临床木糖氧化无色杆菌分离株的全基因组序列。在木糖氧化无色杆菌的不同克隆中，四个编码调节蛋白的基因和两个基因间区域显示出趋同进化，这可能是由致病适应性突变的正选择驱动的。大多数进化后的分离株游动性较低，且对多种抗生素耐药，而与初代分离株相比，进化后的分离株中生长较慢或生物膜产生量较高的较少。使用全基因组关联研究方法，我们在这种病原体中鉴定出了几个生物膜形成、游动性和β-内酰胺耐药性的推定遗传决定因素。关于抗生素耐药性，我们发现致病适应性基因（和）以及另外两个编码调节蛋白的基因（和）中的突变组合与对美罗培南和头孢他啶的耐药性增加有关。总之，我们的结果表明调节位点内的遗传变化促进了木糖氧化无色杆菌在宿主体内的适应性以及适应性表型的出现，如抗生素耐药性或生物膜形成。深入了解细菌病原体的适应性对于治疗慢性细菌感染至关重要。基因组学数据分析和解释中的一个独特挑战是确定在人类宿主定植期间细菌基因组中积累的突变的功能影响。在此，我们研究了木糖氧化无色杆菌在CF患者慢性气道感染中的基因组和表型进化，并使用全基因组关联鉴定了与该病原体表型进化相关的几个突变。鉴定正选择下的表型及相关突变可阐明这种新兴病原体在人类感染中的适应性过程，并为新型治疗干预铺平道路。
