Phage defense mechanisms and their genomic and phenotypic implications in the fish pathogen<i>Vibrio anguillarum</i>

Castillo, Daniel; Rørbo, Nanna; Jørgensen, Jóhanna; Lange, Janina; Tan, Demeng; Kalatzis, Panos G.; Svenningsen, Sine Lo; Middelboe, Mathias

doi:10.1093/femsec/fiz004

Cited by 38 publications

(29 citation statements)

References 55 publications

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“…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 [97,208,[212][213][214][215][216]. 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 [13,119,213,214,[217][218][219]. Such systems-level insights will be valuable both in uncovering new mechanisms in hostphage interaction and perhaps in developing different design strategies for targeted microbial community interventions, engineering highly virulent or extended host-range phages and rationally formulated phage cocktails for therapeutic applications [97,212,215,[220][221][222][223][224][225][226][227][228][229][230][231][232][233].…”

Section: Discussionmentioning

confidence: 99%

High-throughput mapping of the phage resistance landscape in E. coli

et al. 2020

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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 lossof-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 high-throughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phage-mediated 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

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Section: Discussionmentioning

confidence: 99%

High-throughput mapping of the phage resistance landscape in E. coli

et al. 2020

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“…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]. Such systems-level insights will be valuable both in uncovering new mechanisms in host-phage interaction and perhaps in developing different design strategies for targeted microbial community interventions, engineering highly virulent or extended host-range phages and rationally formulated phage-cocktails for therapeutic applications [89,204,208,[213][214][215][216][217][218][219][220][221][222][223][224][225][226].…”

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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“…Yet, bacteria have developed multiple defense mechanisms against phage infections and have stably coexisted among phages in nature [2]. Most bacterial phage resistance inevitably acquires genetic mutations, which is often associated with fitness trade-offs, however, non-mutational defense mechanisms that do not involve genetic changes are also widely distributed, allowing long-term coexistence between bacteria and predators [3,4]. Therefore, a comprehensive understanding of how phages interact with their corresponding host, as well as potential phage resistant mechanisms, is urgently needed, especially with regards to bacteria-phage coevolution in the context of human infections.…”

Section: Introductionmentioning

confidence: 99%

A Frameshift Mutation in wcaJ Associated with Phage Resistance in Klebsiella pneumoniae

et al. 2020

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Phage therapy is a potential and promising avenue for controlling the emergence and spread of multidrug-resistant (MDR) Klebsiella pneumoniae, however, the rapid development of anti-phage resistance has been identified as an obstacle to the development of phage therapy. Little is known about the mechanism employed by MDR K. pneumoniae strains and how they protect themselves from lytic phage predation in vitro and in vivo. In this study, comparative genomic analysis shows undecaprenyl-phosphate glucose-1-phosphate transferase (WcaJ), the initial enzyme catalyzing the biosynthesis of colanic acid, is necessary for the adsorption of phage 117 (Podoviridae) to the host strain Kp36 to complete its lytic life cycle. In-frame deletion of wcaJ alone was sufficient to provide phage 117 resistance in the Kp36 wild-type strain. Complementation assays demonstrated the susceptibility of phage 117, and the mucoid phenotype could be restored in the resistant strain Kp36-117R by expressing the wild-type version of wcaJ. Remarkably, we found that bacterial mobile genetic elements (insA and insB) block phage 117 infections by disrupting the coding region of wcaJ, thus preventing phage adsorption to its phage receptor. Further, we revealed that the wcaJ mutation likely occurred spontaneously rather than adapted by phage 117 predation under unfavorable environments. Taken together, our results address a crucial evolutionary question around the mechanisms of phage–host interactions, increasing our current understandings of anti-phage defense mechanisms in this important MDR pathogen.

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Phage defense mechanisms and their genomic and phenotypic implications in the fish pathogenVibrio anguillarum

Cited by 38 publications

References 55 publications

High-throughput mapping of the phage resistance landscape in E. coli

High-throughput mapping of the phage resistance landscape in E. coli

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

A Frameshift Mutation in wcaJ Associated with Phage Resistance in Klebsiella pneumoniae

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