Persistence and Microevolution of Pseudomonas aeruginosa in the Cystic Fibrosis Lung: A Single-Patient Longitudinal Genomic Study
Persistence and Microevolution of Pseudomonas aeruginosa in the Cystic Fibrosis Lung: A Single-Patient Longitudinal Genomic Study
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DOI：
10.3389/fmicb.2018.03242
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发表时间：
2019-01-11
影响因子：
5.2
通讯作者：
Jousson, Olivier
中科院分区：
文献类型：
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作者：
Bianconi, Irene;D'Arcangelo, Silvia;Jousson, Olivier
背景：铜绿假单胞菌在囊性纤维化(CF)呼吸道持续存在期间，通过积累致病适应性突变而发生一系列表型变化。更好地了解这些突变在适应过程中的作用，特别是多药耐药(MDR)的发展，对于未来开发新的治疗方法至关重要，包括识别新的药物靶点和实施更有效的抗生素治疗。尽管已经发表了几项关于铜绿假单胞菌CF谱系的全基因组测序研究，但与抗菌素耐药性发展相关的进化轨迹至今仍未被探索。在这项研究中，我们监测了铜绿假单胞菌在CF呼吸道微进化过程中的适应性变化，以提供一张创新的全基因组突变和持久表型的图片，并指出潜在的新机制，允许在接受抗生素治疗的CF患者中存活。结果：我们获得了从特伦蒂诺地区支持CF中心(Rovereto，意大利)分离的40株临床铜绿假单胞菌的全基因组序列，这些菌株来自一名CF患者，时间为8年(2007-2014)。对铜绿假单胞菌的基因分型分析表明，该克隆群体由Sequence Type 390和三个密切相关的变异所主导，表明该群体的所有成员可能属于同一克隆谱系，并从一个共同的祖先进化而来。虽然大多数早期分离株对大多数测试的抗生素敏感，但随着时间的推移，持久性人群中耐药表型增加。种群基因组分析表明，铜绿假单胞菌耐药谱的进化与系统发育关系相关，并发现了一些可能的致病适应变异。结论：本研究为铜绿假单胞菌在肺组织中的宿主内适应和微进化提供了有价值的见解，并揭示了随着时间的推移出现的多药耐药表型，这不能用已知耐药基因的变异来全面解释。对本研究中披露的未知变异的进一步研究将有助于我们加深对许多CF患者多药耐药表型的发展和抗生素治疗效果不佳的理解。
Background: During its persistence in cystic fibrosis (CF) airways, P. aeruginosa develops a series of phenotypic changes by the accumulation of pathoadaptive mutations. A better understanding of the role of these mutations in the adaptive process, with particular reference to the development of multidrug resistance (MDR), is essential for future development of novel therapeutic approaches, including the identification of new drug targets and the implementation of more efficient antibiotic therapy. Although several whole-genome sequencing studies on P. aeruginosa CF lineages have been published, the evolutionary trajectories in relation to the development of antimicrobial resistance remain mostly unexplored to date. In this study, we monitored the adaptive changes of P. aeruginosa during its microevolution in the CF airways to provide an innovative, genome-wide picture of mutations and persistent phenotypes and to point out potential novel mechanisms allowing survival in CF patients under antibiotic therapy.Results: We obtained whole genome sequences of 40 P. aeruginosa clinical CF strains isolated at Trentino Regional Support CF Centre (Rovereto, Italy) from a single CF patient over an 8-year period (2007-2014). Genotypic analysis of the P. aeruginosa isolates revealed a clonal population dominated by the Sequence Type 390 and three closely related variants, indicating that all members of the population likely belong to the same clonal lineage and evolved from a common ancestor. While the majority of early isolates were susceptible to most antibiotics tested, over time resistant phenotypes increased in the persistent population. Genomic analyses of the population indicated a correlation between the evolution of antibiotic resistance profiles and phylogenetic relationships, and a number of putative pathoadaptive variations were identified.Conclusion: This study provides valuable insights into the within-host adaptation and microevolution of P. aeruginosa in the CF lung and revealed the emergence of an MDR phenotype over time, which could not be comprehensively explained by the variations found in known resistance genes. Further investigations on uncharacterized variations disclosed in this study should help to increase our understanding of the development of MDR phenotype and the poor outcome of antibiotic therapies in many CF patients.