Abstract
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–phage 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.
Highlights
Fifty years ago, studies on the heterogeneity of genetically uniform populations demonstrated the importance of singlecell individuality for understanding a number of phenomena, including enzyme induction and radiation resistance [1,2,3]
We have shown that the nongenetic individuality in the exit from stationary phase found in populations that persist intensive antibiotic treatments can dramatically affect the interaction between bacteria and k-phages
Persistence to prophage induction could prevent the eradication of lysogenic bacterial populations by prophage induction, and benefit both bacterial hosts and phages in conditions that trigger prophage induction, such as in biofilms and in stressful environments
Summary
Studies on the heterogeneity of genetically uniform populations demonstrated the importance of singlecell individuality for understanding a number of phenomena, including enzyme induction and radiation resistance [1,2,3]. The importance of heterogeneity is evident in the response of bacterial populations to antibiotic treatments, in which most bacteria are rapidly killed, but small subpopulations persist [4]. We directly observed single persister cells in hip strains and determined that persistence is due to an inherent heterogeneity of growth rates in the E. coli population that existed before the antibiotic treatment [9]. Because Type I persisters appear at stationary phase and not during the subsequent exponential growth, their number depends on the size of the inoculum from stationary phase [9,11]. Type I persisters exit their dormant state stochastically and switch to normal growth [9]. Type II persisters are continuously generated during exponential growth and do not require a starvation signal. We focus on Type I persistence, which has been identified as a major factor of persistence to antibiotics in wild-type (wt) E. coli, as well as in Staphylococcus aureus and in Pseudomonas aeruginosa [11]
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