# Live and let die: Lysis time variability and resource limitation shape lytic bacteriophage fitness

## TL;DR

This study shows that variability in bacteriophage lysis times can give them a competitive edge, even if it slows their growth, highlighting the importance of considering such variability in phage research.

## Contribution

The study identifies a novel effect called 'population resonance' where lysis time variability enhances phage fitness in competitive scenarios.

## Key findings

- Phage analytic growth rate in isolation poorly predicts fitness in competition experiments.
- Lysis time variability provides a fitness advantage in serial passage and plaque expansion.
- Models ignoring variability may miss viable evolutionary strategies in phage competition.

## Abstract

Bacteriophages (phages) play a critical role in controlling bacterial populations, both in nature and as potential therapeutic agents. Their ability to replicate, compete against each other, and eradicate target cell populations is usually understood through a number of ‘life history parameters’, traditionally measured by population-level assays, which implicitly average the parameter’s value across a large number of infection events. Recent experiments suggest that bacteriophage life history parameters are subject to considerable stochasticity, raising the question of whether experimental and modelling efforts that do not account for this variability may overlook important factors in phage’s behaviour, competitive fitness or therapeutic viability. Here, using agent-based simulations, we investigate the importance of stochasticity in lysis time and burst size of lytic bacteriophages in two common laboratory competition experiments: serial passage of well-mixed populations and plaque expansion across a bacterial lawn. We find that a phage’s analytic growth rate in isolation can be a poor predictor of its fitness advantage in simulated competition experiments. Specifically, when lysis times are tightly distributed, we identify a novel effect we name “population resonance”, through which a bacteriophage can display a significant fitness advantage over a competitor with a much greater growth rate in isolation. Our simulations also show that both serial passage and plaque expansion reward variability in lysis time more than expected, by increasing the phage resilience when resources are scarce.

Bacteriophages (viruses that infect bacteria) can be described by a set of attributes called ‘life history parameters’. Historically, these parameters could only be measured on-average over large populations. Recent experimental advancements, however, have enabled their quantification at the single-cell-single-virus level, and have revealed that these traits are subject to inherent variability, even for genetically identical viruses infecting genetically identical cells. Here, we explore whether the degree of variability in two particular life history parameters; the lysis time (the time taken for a bacteriophage to infect and kill its host bacterium) and burst size (the number of new viruses produced per infected bacterium) might be subject to natural selection, by quantifying their effects on a phage’s fitness in two simulated competition experiments: serial passage and plaque expansion. Surprisingly, we find that lysis time variability is advantageous in competition even when it reduces the phage’s growth rate in isolation. This finding opens the door to future computational and experimental work, as it demonstrates that mean values alone are not sufficient to describe or predict a bacteriophage efficacy, and that models that ignore this variability can overlook viable evolutionary strategies.