Phenotypic flux: The role of physiology in explaining the conundrum of bacterial persistence amid phage attack

Bacteriophages, the viruses of bacteria, have been studied for over a century. They were not only instrumental in laying the foundations of molecular biology, but they are also likely to play crucial roles in shaping our biosphere and may offer a solution to the control of drug-resistant bacterial infections. However, it remains challenging to predict the conditions for bacterial eradication by phage predation, sometimes even under well-defined laboratory conditions, and, most curiously, if the majority of surviving cells are genetically phage-susceptible. Here, I propose that even clonal phage and bacterial populations are generally in a state of continuous ‘phenotypic flux’, which is caused by transient and nongenetic variation in phage and bacterial physiology. Phenotypic flux can shape phage infection dynamics by reducing the force of infection to an extent that allows for coexistence between phages and susceptible bacteria. Understanding the mechanisms and impact of phenotypic flux may be key to providing a complete picture of phage–bacteria coexistence. I review the empirical evidence for phenotypic variation in phage and bacterial physiology together with the ways they have been modeled and discuss the potential implications of phenotypic flux for ecological and evolutionary dynamics between phages and bacteria, as well as for phage therapy.