Nongenetic Individuality in the Host�CPhage Interaction

Isogenic bacteria can exhibit a range of phenotypes, even in homogeneous environmental conditions. Such nongenetic individuality has been observed in a wide range of biological processes, including differentiation and stress response. A striking example is the heterogeneous response of bacteria to antibiotics, whereby a small fraction of drug-sensitive bacteria can persist under extensive antibiotic treatments. We have previously shown that persistent bacteria enter a phenotypic state, identified by slow growth or dormancy, which protects them from the lethal action of antibiotics. Here, we studied the effect of persistence on the interaction between Escherichia coli and phage lambda. We used long-term time-lapse microscopy to follow the expression of green fluorescent protein (GFP) under the phage lytic promoter, as well as cellular fate, in single infected bacteria. Intriguingly, we found that, whereas persistent bacteria are protected from prophage induction, they are not protected from lytic infection. Quantitative analysis of gene expression reveals that the expression of lytic genes is suppressed in persistent bacteria. However, when persistent bacteria switch to normal growth, the infecting phage resumes the process of gene expression, ultimately causing cell lysis. Using mathematical models for these two host�Cphage interactions, we found that the bacteria's nongenetic individuality can significantly affect the population dynamics, and might be relevant for understanding the coevolution of bacterial hosts and phages.

即使在均质的环境条件下，同基因细菌（isogenic bacteria）仍可表现出多样的表型。这种非遗传个体差异已在包括分化与应激反应在内的多种生物过程中被观测到。其中一个极具代表性的例子是细菌对抗生素的异质性应答：小部分药敏细菌可在高强度抗生素处理下持续存活。我们此前的研究表明，持留细菌会进入以生长缓慢或休眠为特征的表型状态，该状态可使其免受抗生素的致死性杀伤。本研究探讨了持留性对大肠杆菌（Escherichia coli）与λ噬菌体（phage lambda）相互作用的影响。我们借助长期延时显微镜技术，追踪了单个受感染细菌中噬菌体裂解启动子调控下的绿色荧光蛋白（GFP）表达情况，以及细胞命运的变化。有趣的是，我们发现持留细菌可免受原噬菌体诱导的影响，但无法抵御裂解性感染。基因表达定量分析显示，持留细菌内的裂解基因表达受到抑制。然而，当持留细菌恢复正常生长后，感染的噬菌体会重新启动基因表达过程，最终导致细胞裂解。通过针对这两类宿主-噬菌体相互作用构建数学模型，我们发现细菌的非遗传个体差异可显著影响种群动态，这或许有助于解析细菌宿主与噬菌体的共进化机制。