Phage resistance evolution
            <i>in vitro</i>
            is not reflective of
            <i>in vivo</i>
            outcome in a plant‐bacteria‐phage system*

Hernandez, Catherine A.; Koskella, Britt

doi:10.1111/evo.13833

Cited by 61 publications

(64 citation statements)

References 86 publications

(163 reference statements)

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“…The screening technologies presented in this work are scalable to study phage resistance in diverse conditions that simulate the natural environment and may provide valuable insights on host fitness and host-phage co-evolutionary dynamics under more ecologically relevant conditions. For example, recent studies highlighted the evidence of subdued phage resistance in the natural environment, probably because of the fitness cost associated with resistance mechanisms [89,[204][205][206][207][208][209]. In addition, these methods have the capability to identify fitness costs associated with broadly seen phage resistance phenotypes in a competitive natural environment, and thus improve our understanding of microbial ecology in general [13,114,206,207,[210][211][212].…”

Section: Discussionmentioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and highthroughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phagemediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.3 Introduction:

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Section: Discussionmentioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

Self Cite

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“…The arms race may involve a few steps of phages evolving to overcome bacterial resistance and new bacterial resistance evolving, but ultimately a bacterial resistance evolves that cannot be overcome by phage evolution; phage are subsequently lost or their abundance greatly suppressed. This simple story is often violated when bacteria are grown under more complex in vitro environments or in natural ones: resistant bacteria may fail to ascend, with the phage persisting and permanently suppressing the bacteria [65,66]. However, other outcomes have also been observed [61,62,64].…”

Section: Resultsmentioning

confidence: 99%

Promises and pitfalls ofin vivoevolution to improve phage therapy

Bull

Levin

Molineux

2019

Preprint

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Background) Phage therapy is the use of bacterial viruses (phages) to treat bacterial 1 infections. Phages lack the broad host ranges of antibiotics, so individual phages are often used with 2 no prior history of use in treatment. Therapeutic phages are thus often chosen based on limited 3 criteria, sometimes merely an ability to plate on the pathogenic bacterium. It is possible that better 4 treatment outcomes might be obtained from an informed choice of phages. Here we consider whether 5 phages used to treat the bacterial infection in a patient might specifically evolve to improve treatment. 6 Phages recovered from the patient could then serve as a source of improved phages or cocktails for 7 use on subsequent patients. (Methods) With the aid of mathematical and computational models, we 8 explore this possibility for four phage properties expected to promote therapeutic success: in vivo 9 growth, phage decay rate, overcoming resistant bacteria, and enzyme activity to degrade protective 10 bacterial layers. (Results) Phage evolution only sometimes works in favor of treatment, and even in 11 those cases, intrinsic phage dynamics in the patient are usually not ideal. An informed use of phages 12is invariably superior to reliance on within-host evolution and dynamics, although the extent of this 13 benefit varies with the application. 14

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“…The arms race may involve a few steps of phages evolving to overcome bacterial resistance and new bacterial resistance evolving, but ultimately a bacterial resistance evolves that cannot be overcome by phage evolution; phage are subsequently lost or their abundance greatly suppressed. This simple story is often violated when bacteria are grown under more complex in vitro environments or in natural ones: resistant bacteria may fail to ascend, with the phage persisting and permanently suppressing the bacteria [79,80]. However, other outcomes have also been observed [65,66,68].…”

Section: Phage Evolution To Overcome Bacterial Resistancementioning

confidence: 99%

Promises and Pitfalls of In Vivo Evolution to Improve Phage Therapy

Bull

Levin

Molineux

2019

Viruses

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Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages.Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.

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Phage resistance evolution in vitro is not reflective of in vivo outcome in a plant‐bacteria‐phage system*

Cited by 61 publications

References 86 publications

High-throughput mapping of the phage resistance landscape inE. coli

High-throughput mapping of the phage resistance landscape inE. coli

Promises and pitfalls ofin vivoevolution to improve phage therapy

Promises and Pitfalls of In Vivo Evolution to Improve Phage Therapy

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