Capsid and Tail

a weekly phage periodical
Issue 18: Studying phage-host coevolution
February 22, 2019

Studying phage-host coevolution in the lab

How is phage-host coevolution studied in the lab, and what can it tell us?

This week, we highlight a new paper by Stephen Wandro and colleagues in the Whiteson and Martiny labs at the University of California, Irvine. The paper describes a clear, highly informative phage-host coevolution study they’ve done with an Enterococcus faecium phage-host pair.

What's New

Check out this extremely informative Twitter thread by Simon Roux, which breaks down his new preprint on the pervasiveness of Inoviruses. Detect Inoviruses in your own sequence data with this tool (Github). We want to encourage more scientists to break down their studies like this, so if you find examples, let us know and we’ll highlight them!

Best of phage twitterInovirusesBioinformatics

Carol E. Zhou and colleagues report a new phage annotation pipeline called multiPhATE. Preprint and Github.

BioinformaticsPhage annotation

A new virome twin study! J. Leonardo Moreno-Gallego and colleagues show that virome and microbiome diversity correlate, and in contrast to a prior study, adult twins DO have more similar viromes than unrelated individuals. They suggest that microbiome diversity in study subjects should be balanced before viromes are assessed.

Gut viromeGut microbiomeResearch

Rob Lavigne at KU Leuven is seeking comments on his new preprint on patents related to phage use in agriculture. Comment under the paper on BioRxiv, or tweet @RobLavigne1!

PreprintPatenting phagesPhages in agriculture

This commentary by Jens H. Kuhn and colleagues may convince you to care more about the need for cataloguing viral genomes.

Viral genomesICTV

Great news for BiomX, a company developing custom phage therapies to treat microbiome-based diseases, which just raised $32 million in series B financing!

BiotechMicrobiome

Latest Jobs

Postdoctoral position: Phage display / neurodegeneration
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Dr. Adam Martin

The Dementia Research Centre within the Department of Biomedical Sciences is seeking a suitably qualified Postdoctoral Research Fellow with a proven track record in peptide phage display technology to provide research support for the NHMRC funded project “Self-assembled hydrogels for neurodegeneration”.

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A post-doctoral fellowship is available in the University of Edinburgh with Professor J. Ross Fitzgerald and colleagues. The 3 year-funded project involves a grouping of microbiologists, bioinformaticians and veterinary and human medical clinicians in the Roslin Institute, University of Edinburgh. We have demonstrated the capacity for Nanopore-based whole genome sequencing of clinical samples without the need for culture, to allow rapid diagnosis of bacterial infections and prediction of antibiotic sensitivity. The successful candidate will further develop the sequence-based technique which will be formally tested on veterinary patients with infections in a clinical setting.

*Note from Twitter: this position will involve working alongside a group doing phage therapy research

Post Doc Computational biologyBacterial Genomics

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February 22, 2019
Seeking feedback on a new phage susceptibility testing platform
Name: Michael Van Delle
Organization: Adventus Research + Consulting

University of Toronto researchers have developed a novel phage susceptibility testing platform. To understand the need for such a solution, Adventus Research + Consulting is reaching out to phage community experts, stakeholders and researchers for feedback. Honoraria are offered in exchange for your feedback (either via phone or survey). Email Michael Van Belle at [email protected] to participate!

Request for feedback Phage SusceptibilityNew technologyExpired

Studying phage-host coevolution in the lab

Raise your hand if you’ve used the terms “coevolution” or “arms race” to describe how phages and their hosts interact. Chances are, if you’ve written a grant, a paper, an abstract or a scholarship application about phages, you’ve done it. But how is this actually measured in the lab, and what can it tell us?

The problem:

Collectively, we don’t know much about phage-host interactions on a molecular level, but we’re already using phages to treat antibiotic-resistant infections and making plans to use phages to manipulate the microbiome. This is a problem that can (and should) be fixed.

For most phages:

  • We don’t know which parts of their hosts are important for phage infection (e.g. bacterial surface receptors are unknown)
  • We don’t know how bacteria evolve phage resistance (what do they change about themselves?), nor do we know much about the properties of phage-resistant bacteria (are they more or less pathogenic? More or less antibiotic-susceptible?)
  • We don’t know how phages respond to these newly-evolved phage-resistant bacteria

The paper:

Stephen Wandro and colleagues have elegantly shown how they’ve come closer to answering these questions for a strain of Enterococcus faecium and a phage that targets this pathogen.

First of its kind?

This isn’t the first time this kind of experiment has been done on a phage-host pair (E. coli and Pseudomonas fluorescens have been well-studied in this manner), but this group has done it using an opportunistic gut pathogen (isolated from human stool). This is especially interesting because we don’t know much about phage-host interactions in the gut yet.

A few things up front:

  • Everything was done in vitro, and the authors studied one bacterial strain and one phage.
  • The bacterial host: Enterococcus faecium (isolated from human stool, obtained from BEI Resources)
  • The phage: a Myovirus called EfV12-phi1 (isolated from sewage; obtained from the Felix d’Herelle Center)

The experiment:

  • Grow phage and bacteria together. Twice a day for about a week (~53 generations total), transfer some of the mixture to a flask of fresh growth medium. Follow bacterial growth dynamics / phage susceptibility over time. At the same time, track phage and bacterial sequences to watch which genes change.
  • The controls: 1) Do the same, except transfer just the phages to naïve bacteria each time (follow what happens when only the phage is allowed to evolve). 2) Do the same with bacteria grown on their own (follow changes in the bacteria that have nothing to do with the phage).
  • Their hypothesis: that they’d see changes in phage tail fibers and bacterial surface receptors over time.

(Some of) what they found:

Coevolution dynamics:
  • When the host was allowed to evolve alongside the phage, one of two things happened: phage-resistant cells emerged, then were overcome by the evolving phage, then new phage-resistant cells re-emerged, OR phage-resistant mutant cells emerged and then held strong, with no further population crashes
  • When phages were introduced onto naïve hosts each time, the phage population was soon able to consistently clear the culture
Host genome changes:
  • Mutations in the host consistently accumulated in two genes: yqwD2 (capsular polysaccharide production) and rpoC (RNA polymerase)
Phage genome changes:
  • Regardless of whether the bacteria were allowed to evolve or not, three phage genes were consistently altered: a capsid gene and two hypothetical genes.
  • There was one phage mutation that consistently occurred ONLY when the host was allowed to co-evolve: this was a duplication of a portion of the tail fiber gene.

In conclusion:

Not only did this group show coevolutionary dynamics of a new phage-host pair representing an understudied, clinically-relevant pathogen, but they showed exactly which genes change over time during this coevolution. Importantly, these dynamics were predictable.

As a bonus, they highlighted an unexpected mechanism by which the phage is able to alter its tail fiber gene, and their results suggest that this might happen in response to the host altering its extracellular sugars (capsule).

So many new questions!

Does this mean the phage receptor is part of the host’s capsule? Does the host become more or less pathogenic (or more or less antibiotic resistant) when it evolves changes in its capsule genes? What happens if you combine this phage with a phage that DOESN’T provoke changes in the capsule, but instead leads to changes in something else… is the cell able to manage? What happens if you combine this phage with an antibiotic that targets RNA polymerase? Do the phage-induced changes in rpoC alter the cell’s susceptibility to the drug?

Let’s do more experiments like this one!

Doing studies like this one with other phage-host pairs will give us the power to more accurately predict phage-bacterial interaction outcomes. Armed with this kind of insight, we’ll be better able to make decisions about which phages to use on which pathogens, and whether or not to combine them with antibiotics, other phages, both, or neither.

Thoughts?

Phage researchers and those in the phage therapy industry: are you doing these kinds of experiments on your favourite phages? Why or why not? Email us at [email protected] or tweet @phagedirectory using the hashtag #coevolution if you’d like to weigh in.

Thanks for reading!
– Jessica <>={

Main Source:

Wandro et al. 2019. Predictable Molecular Adaptation of Coevolving Enterococcus faecium and Lytic Phage EfV12-phi1. Frontiers in Microbiology.

Jessica Sacher is a co-founder of Phage Directory and has a Ph.D in Microbiology and Biotechnology

For every issue of Capsid & Tail, we are committed to getting our facts straight, but we’re not experts in the information we’re bringing to you. If you feel that we’ve missed an important viewpoint, or if you have something to add, please reach out to us by emailing [email protected]. We’d love to hear from you, and we’d be happy to revisit topics we’ve covered (ideally with added information and viewpoints from community members like you!).

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