Parallel evolution of Pseudomonas aeruginosa phage resistance and virulence loss in response to phage treatment in vivo and in vitro.
Parallel evolution of Pseudomonas aeruginosa phage resistance and virulence loss in response to phage treatment in vivo and in vitro.
复制标题
铜绿假单胞菌噬菌体耐药性和毒力丧失在体内和体外对噬菌体处理的平行进化
DOI：
10.7554/elife.73679
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发表时间：
2022-02-21
期刊：
影响因子：
7.7
通讯作者：
Buckling A
中科院分区：
文献类型：
--
作者：
Castledine M;Padfield D;Sierocinski P;Soria Pascual J;Hughes A;Mäkinen L;Friman VP;Pirnay JP;Merabishvili M;de Vos D;Buckling A
随着抗生素耐药性的增加，人们对用噬菌体治疗致病菌（噬菌体治疗）越来越感兴趣。噬菌体疗法的一个局限是细菌很容易进化出耐药性。当耐药性导致细菌生长和毒力减少，或者当噬菌体共同进化以克服耐药性时，耐药性的负面影响可能会减轻。耐药进化及其后果取决于细菌噬菌体组合及其环境背景，使得治疗结果难以预测。一种解决方案可能是使用来自治疗环境的细菌噬菌体组合进行“体外进化模拟”。总的来说，我们的目的是研究体外实验和人类参与者体内动力学之间的相似之处。进化动力学相似，高水平的耐药性进化迅速，噬菌体进化的证据有限。耐药细菌——在体内和体外进化——具有较低的毒力。在体内，这与耐药菌株生长速度较低有关，而在体外，噬菌体耐药菌株进化出更大的生物膜产量。种群测序表明，抗性来自于对新生突变的选择，而不是对现有变异的分类。这些结果突出了噬菌体耐药性在体内进化的速度，以及体外实验如何为临床进化结果提供有用的见解。
With rising antibiotic resistance, there has been increasing interest in treating pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. Negative effects of resistance may be mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolves to overcome resistance. Resistance evolution and its consequences are contingent on the bacteria-phage combination and their environmental context, making therapeutic outcomes hard to predict. One solution might be to conduct ‘in vitro evolutionary simulations’ using bacteria-phage combinations from the therapeutic context. Overall, our aim was to investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar, with high levels of resistance evolving quickly with limited evidence of phage evolution. Resistant bacteria—evolved in vitro and in vivo—had lower virulence. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro phage resistant isolates evolved greater biofilm production. Population sequencing suggests resistance resulted from selection on de novo mutations rather than sorting of existing variants. These results highlight the speed at which phage resistance can evolve in vivo, and how in vitro experiments may give useful insights for clinical evolutionary outcomes.