Bacteriophages of the Human Gut: The “Known Unknown” of the Microbiome

Shkoporov, Andrey N.; Hill, Colin

doi:10.1016/j.chom.2019.01.017

Cited by 463 publications

(401 citation statements)

References 112 publications

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“…Bacterial viruses, or bacteriophages (phages), are obligate parasites that infect specific bacterial strains. Phages represent the most abundant biological entities on earth, and are key ecological drivers of microbial community dynamics, activity and adaptation; thereby impacting environmental nutrient cycles, agricultural output, and human and animal health [1][2][3][4][5][6][7][8]. Despite nearly a century of pioneering molecular work, the mechanistic insights into phage specificity for a given host, infection pathways, and the breadth of bacterial responses to different phages have largely focused on a handful of individual bacterium-phage systems [9][10][11][12][13].…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

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

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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“…Lytic phages are abundant in natural environments including marine ecosystems (16) and gut microbiomes (17), making LIN a relevant tool in the molecular arsenal of lytic phages infecting bacteria like Vibrio cholerae. Vibrio cholerae causes a substantial global health problem as the causative agent of the diarrheal disease cholera (18).…”

Section: Introductionmentioning

confidence: 99%

DominantVibrio choleraephage exhibits lysis inhibition sensitive to disruption by a defensive phage satellite

Hays

Seed

2019

Preprint

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AbstractBacteriophages and their bacterial hosts are locked in a dynamic evolutionary arms race. Phage satellites, selfish genomic islands which exploit both host bacterium and target phage, further complicate the evolutionary fray. One such tripartite system involves the etiological agent of the diarrheal disease cholera – Vibrio cholerae, the predominant phage isolated from cholera patients – ICP1, and a phage satellite – PLE. When ICP1 infects V. cholerae harboring the integrated PLE genome, PLE accelerates host lysis, spreading the PLE while completely blocking phage production protecting V. cholerae at the population level. Here we identify a single PLE gene, lidI, sufficient to mediate accelerated lysis during ICP1 infection and demonstrate that LidI functions through disrupting lysis inhibition – an understudied outcome of phage infection when phages vastly outnumber their hosts. This work identifies ICP1-encoded holin and antiholin genes teaA and arrA respectively, that mediate this first example of lysis inhibition outside the T-even coliphages. Through lysis inhibition disruption, LidI is sufficient to limit the number of progeny phage produced from an infection. Consequently, this disruption bottlenecks ICP1 evolution as probed by recombination and CRISPR-Cas targeting assays. These studies link novel characterization of the classic phenomenon of lysis inhibition with a conserved protein in a dominant phage satellite, highlighting the importance of lysis timing during infection and parasitization, as well as providing insight into the populations, relationships, and evolution of bacteria, phages, and phage satellites in nature.ImportanceWith increasing awareness of microbiota impacting human health comes intensified examination of, not only bacteria and the bacteriophages that prey upon them, but also the mobile genetic elements (MGEs) that mediate interactions between them. Research is unveiling evolutionary strategies dependent on sensing the milieu: quorum sensing impacts phage infection, phage teamwork overcomes bacterial defenses, and abortive infections sacrifice single cells protecting populations. Yet, the first discovered environmental sensing by phages, known as lysis inhibition (LIN), has only been studied in the limited context of T-even coliphages. Here we characterize LIN in the etiological agent of the diarrheal disease cholera, Vibrio cholerae, infected by a phage ubiquitous in clinical samples. Further, we show that a specific MGE, the phage satellite PLE, collapses LIN with a conserved protein during its anti-phage program. The insights gleaned from this work add to our expanding understanding of microbial fitness in natural contexts beyond the canonical bacterial genome and into the realm of antagonistic evolution driven by phages and satellites.

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“…Death rates will be affected by the presence of toxic substances to which the species is susceptible (e.g. bile acids, antimicrobial peptides, antimicrobials produced by other species in the microbiota) and phage (either reactivation of dormant prophage or lytic infection) . It is worth noting that dead bacteria may act as a sink for specific antibodies.…”

Section: Host Intestinal Physiology and The Microbiotamentioning

confidence: 99%

Growing, evolving and sticking in a flowing environment: understanding IgA interactions with bacteria in the gut

et al. 2019

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Summary Immunology research in the last 50 years has made huge progress in understanding the mechanisms of anti‐bacterial defense of deep, normally sterile, tissues such as blood, spleen and peripheral lymph nodes. In the intestine, with its dense commensal microbiota, it seems rare that this knowledge can be simply translated. Here we put forward the idea that perhaps it is not always the theory of immunology that is lacking to explain mucosal immunity, but rather that we have overlooked crucial parts of the mucosal immunological language required for its translation: namely intestinal and bacterial physiology. We will try to explain this in the context of intestinal secretory antibodies (mainly secretory IgA), which have been described to prevent, to alter, to not affect, or to promote colonization of the intestine and gut‐draining lymphoid tissues, and where effector mechanisms have remained elusive. In fact, these apparently contradictory outcomes can be generated by combining the basic premises of bacterial agglutination with an understanding of bacterial growth (i.e. secretory IgA‐driven enchained growth), fluid handling and bacterial competition in the gut lumen.

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Bacteriophages of the Human Gut: The “Known Unknown” of the Microbiome

Cited by 463 publications

References 112 publications

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

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

DominantVibrio choleraephage exhibits lysis inhibition sensitive to disruption by a defensive phage satellite

Growing, evolving and sticking in a flowing environment: understanding IgA interactions with bacteria in the gut

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