中文摘要：食用受空肠弯曲杆菌(C. jejuni)污染的禽肉会引起胃肠炎，这在世界范围内造成巨大的健康和经济负担。噬菌体治疗很有前途，可根除禽肉中的空肠弯曲杆菌。然而，空肠弯曲杆菌可以通过简单重复序列(SSR)介导噬菌体受体随机、相变开/关转换来抵抗某些噬菌体的感染。虽然选择强度和暴露时间对SSR介导的相变（PV）进化有影响，但噬菌体的复制依赖于宿主生物体，因而进化环境更复杂。本研究建立并探索了几个连续培养的噬菌体计算模型，每种模型都分析不同的相变场景，以空肠弯曲杆菌位点的实验SSR率和F336噬菌体的复制参数进行校准。通过自适应动力学框架模拟了不同水平的选择性压力作用于噬菌体抗性状态下PV率的演变。结果表明，在单个PV位点上，生长抑制反选择可维持噬菌体的稳定，而细菌状态间的补偿选择影响进化稳定突变率（即过高和过低的突变率对进化不利）；但是，在没有任何选择压力的情况下，PV率的进化导致突变率低于基本值。相反，具有两个相变位点的生物相关模型导致噬菌体灭绝并将细菌锁定到噬菌体抗性状态，这表明需要另一个反选择压力，例如使用受体为F336噬菌体抗性状态的独特噬菌体。可见，反选择和噬菌体攻击之间的微妙平衡可导致相变噬菌体受体的进化和PV受体特异性噬菌体的持久性。
作者总结：全球抗生素耐药性的上升重新引起了人们对噬菌体疗法的兴趣。噬菌体作用于细菌以选择抗性机制，如通过相变（PV）丧失噬菌体受体。相变基因通过基因表达的随机转换介导快速适应。空肠弯曲杆菌是鸟类常见的共生菌，但也会引起人体严重的胃肠道感染。用噬菌体治疗空肠弯曲杆菌，首先需要深入了解PV如何进化并介导噬菌体抗性。本研究使用详细的连续培养模型来研究营养受限的细菌-噬菌体相互作用，并校准了PV率，以匹配对空肠弯曲杆菌和噬菌体F336的实验观察。在考虑到两个相变位点的模型中，当对所有抗噬菌体状态施加生长抑制反选择时，进化与实验结果紧密匹配；而仅限于对免疫效应物抗性相关的特定状态施加生长抑制反选择时，进化与实验结果不匹配。。可见，单个和多个不同的噬菌体施加的选择压力的微妙平衡是利用噬菌体有效治疗空肠弯曲杆菌所必须的。
 
外文摘要：Campylobacter jejuni (C. jejuni) causes gastroenteritis following the consumption of contaminated poultry meat, resulting in a large health and economic burden worldwide. Phage therapy is a promising technique for eradicating C. jejuni from poultry flocks and chicken carcasses. However, C. jejuni can resist infections by some phages through stochastic, phase-variable ON/OFF switching of the phage receptors mediated by simple sequence repeats (SSR). While selection strength and exposure time influence the evolution of SSR-mediated phase variation (PV), phages offer a more complex evolutionary environment as phage replication depends on having a permissive host organism. Here, we build and explore several continuous culture bacteria-phage computational models, each analysing different phase-variable scenarios calibrated to the experimental SSR rates of C. jejuni loci and replication parameters for the F336 phage. We simulate the evolution of PV rates via the adaptive dynamics framework for varying levels of selective pressures that act on the phage-resistant state. Our results indicate that growth reducing counter-selection on a single PV locus results in the stable maintenance of the phage, while compensatory selection between bacterial states affects the evolutionary stable mutation rates (i.e. very high and very low mutation rates are evolutionarily disadvantageous), whereas, in the absence of either selective pressure the evolution of PV rates results in mutation rates below the basal values. Contrastingly, a biologically-relevant model with two phase-variable loci resulted in phage extinction and locking of the bacteria into a phage-resistant state suggesting that another counter-selective pressure is required, for instance the use of a distinct phage whose receptor is an F336-phage-resistant state. We conclude that a delicate balance between counter-selection and phage-attack can result in both the evolution of phase-variable phage receptors and persistence of PV-receptor-specific phage.
Author summary Globally rising rates of antibiotic resistance have renewed interest in phage therapy. Bacteriophages (phages) act on bacteria to select for resistance mechanisms such as loss of phage receptors by phase variation (PV). Phase-variable genes mediate rapid adaption by stochastic switching of gene expression. Campylobacter jejuni is a common commensal of birds but also causes serious gastrointestinal infections in humans. Optimisation of phage therapy against C. jejuni, requires an in-depth understanding of how PV has evolved and mediates phage resistance. Here, we use a detailed continuous culture model for nutrient-limited bacteria-phage interactions, with PV rates calibrated to match the experimental observations for C.jejuni and phage F336. Evolution within a model accounting for two phase-variable loci closely matches the experimental results when growth reducing counter-selection is imposed on all phage-resistant states, but, not when restricted to the particular states associated with resistance to immune effectors. Our results emphasize that delicate balancing of selective pressures, imposed by single and multiple distinct phages, are necessary for effective use of phage therapy against C. jejuni.
外文关键词：COMPLETE GENOME SEQUENCE；BACTERIOPHAGE INFECTION；ANTIGENIC VARIATION；MISMATCH REPAIR；MUTATION-RATES；VARIABLE GENES；VIRULENT PHAGE；JEJUNI；BACTERIAL; MODEL
作者：Sandhu, SK；Bayliss, CD；Morozov, AY
作者单位：Univ Leicester；Russian Acad Sci
期刊名称：PLOS COMPUTATIONAL BIOLOGY
期刊影响因子：4.7
出版年份：2021
出版刊次：6
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