How does feedback from phage infections influence the evolution of phase variation in Campylobacter?
How does feedback from phage infections influence the evolution of phase variation in Campylobacter?
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噬菌体感染产生的反馈是如何影响弯曲杆菌相变进化的？
DOI：
10.1371/journal.pcbi.1009067
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发表时间：
2021-06
影响因子：
4.3
通讯作者：
Morozov AY
中科院分区：
文献类型：
--
作者：
Sandhu SK;Bayliss CD;Morozov AY
空肠弯曲菌（C. jejuni）会在人们食用受污染的禽肉后引发肠胃炎，在全球范围内造成巨大的健康和经济负担。噬菌体疗法是一种很有前景的技术，可用于清除家禽群体和鸡屠体中的空肠弯曲菌。然而，空肠弯曲菌能够通过由简单序列重复（SSR）介导的噬菌体受体的随机、相位可变的开/关切换，来抵御某些噬菌体的感染。虽然选择强度和暴露时间会影响SSR介导的相位变异（PV）的进化，但噬菌体提供了一个更为复杂的进化环境，因为噬菌体的复制依赖于存在允许其感染的宿主生物。在此，我们构建并探究了几种连续培养细菌 - 噬菌体计算模型，每个模型都分析了不同的相位可变场景，这些场景根据空肠弯曲菌基因座的实验SSR速率以及F336噬菌体的复制参数进行了校准。我们通过适应性动力学框架，针对作用于噬菌体抗性状态的不同选择压力水平，模拟了PV速率的进化。我们的结果表明，对单个PV基因座施加降低生长的反向选择会导致噬菌体的稳定维持，而细菌状态之间的补偿性选择会影响进化稳定的突变率（即极高和极低的突变率在进化上都是不利的），然而，在没有任何一种选择压力的情况下，PV速率的进化会导致突变率低于基础值。相比之下，一个具有两个相位可变基因座的生物学相关模型导致噬菌体灭绝，并且细菌锁定在噬菌体抗性状态，这表明需要另一种反向选择压力，例如，使用其受体为F336噬菌体抗性状态的不同噬菌体。我们得出结论，反向选择与噬菌体攻击之间的微妙平衡，既能导致相位可变噬菌体受体的进化，也能使PV受体特异性噬菌体持续存在。
全球范围内抗生素耐药率的上升，重新引发了人们对噬菌体疗法的兴趣。噬菌体作用于细菌，促使细菌产生诸如通过相位变异（PV）丧失噬菌体受体等抗性机制。相位可变基因通过基因表达的随机切换介导快速适应。空肠弯曲菌是鸟类常见的共生菌，但也会在人类中引发严重的胃肠道感染。优化针对空肠弯曲菌的噬菌体疗法，需要深入了解PV是如何进化以及如何介导噬菌体抗性的。在此，我们使用一个详细的连续培养模型来研究营养限制条件下细菌 - 噬菌体的相互作用，其中PV速率经过校准，以匹配空肠弯曲菌和噬菌体F336的实验观察结果。当对所有噬菌体抗性状态施加降低生长的反向选择时，考虑两个相位可变基因座的模型内的进化与实验结果紧密匹配，但当反向选择仅限于与免疫效应物抗性相关的特定状态时则不然。我们的结果强调，为了有效利用噬菌体疗法对抗空肠弯曲菌，由单个和多个不同噬菌体施加的选择压力之间的微妙平衡是必要的。
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, 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. 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.
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影响因子：
4.6
作者：
Egilmez HI;Morozov AY;Clokie MRJ;Shan J;Letarov A;Galyov EE
通讯作者：
Galyov EE
DOI：
10.1038/nrmicro2145
发表时间：
2009-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0600166103
发表时间：
2006-03-21
影响因子：
11.1
作者：
Jensen, MA;Faruque, SM;Levin, BR
通讯作者：
Levin, BR
影响因子：
3.6
作者：
Karlyshev, AV;Champion, OL;Szymanski, CM
通讯作者：
Szymanski, CM
影响因子：
1.9
作者：
Gourley, SA;Kuang, Y
通讯作者：
Kuang, Y