A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes

Dutilh, Bas E.; Cassman, Noriko A.; McNair, Katelyn; Sanchez, Savannah E.; Silva, Genivaldo G. Z.; Boling, Lance; Barr, Jeremy J.; Speth, Daan R.; Seguritan, Victor; Aziz, Ramy K.; Felts, Ben; Dinsdale, Elizabeth A.; Mokili, John L.; Edwards, Robert A.

doi:10.1038/ncomms5498

Cited by 688 publications

(861 citation statements)

References 69 publications

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“…Similar protein domains are encoded by ∼25% of the known members of the predominant order of phages (Caudovirales) (47). Given the enormous diversity of phages associated with mucosal surfaces, we expect many will be found to use Ig-like proteins or other carbohydrate-adherent surface proteins to increase their replicative success via subdiffusive motion (48)(49)(50). Furthermore, we speculate that their mucin-binding is finely tuned to position the phage particles in the optimal mucus zone where their bacterial hosts reside, further increasing encounter rates.…”

Section: Discussionmentioning

confidence: 99%

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters

Barr

Auro

Sam-Soon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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181

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Bacteriophages (phages) defend mucosal surfaces against bacterial infections. However, their complex interactions with their bacterial hosts and with the mucus-covered epithelium remain mostly unexplored. Our previous work demonstrated that T4 phage with Hoc proteins exposed on their capsid adhered to mucin glycoproteins and protected mucus-producing tissue culture cells in vitro. On this basis, we proposed our bacteriophage adherence to mucus (BAM) model of immunity. Here, to test this model, we developed a microfluidic device (chip) that emulates a mucosal surface experiencing constant fluid flow and mucin secretion dynamics. Using mucus-producing human cells and Escherichia coli in the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4Δhoc phage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4Δhoc phage. This suggests that phage adherence to mucus increases encounters with bacterial hosts by some other mechanism. Phages are traditionally thought to be completely dependent on normal diffusion, driven by random Brownian motion, for host contact. We demonstrated that T4 phage particles displayed subdiffusive motion in mucus, whereas T4Δhoc particles displayed normal diffusion. Experiments and modeling indicate that subdiffusive motion increases phage-host encounters when bacterial concentration is low. By concentrating phages in an optimal mucus zone, subdiffusion increases their host encounters and antimicrobial action. Our revised BAM model proposes that the fundamental mechanism of mucosal immunity is subdiffusion resulting from adherence to mucus. These findings suggest intriguing possibilities for engineering phages to manipulate and personalize the mucosal microbiome.BAM | virus | mucus | subdiffusion | search strategy I n all animals, mucosal surfaces provide critical immunological services by both protecting against invading bacterial pathogens and supporting large communities of commensal microorganisms (1, 2). Being exposed to the environment, mucosal surfaces are also the infection sites for many important bacterial diseases, including acute diarrhea and cystic fibrosis in humans. This, combined with their accessibility, make mucosal surfaces attractive venues for phage therapy; that is, the use of bacteriophages (phages) to treat and clear bacterial infections (3,4). Clinical success so far has been erratic (5). The complexities and dynamics of the mucus layer are rarely considered, and the activity of phages therein is mostly unknown. Not surprisingly, phages effective in vitro do not consistently reduce mucosal bacterial host levels in vivo (6, 7). An understanding of the interactions between phages and their bacterial hosts within the relevant physiological environment is critical for consistent success of phage therapy applications.The multilayered mucus is composed primarily of gel-forming mucin glycoproteins that are continually secreted by the underlying epithelium (8). The mucin...

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Section: Discussionmentioning

confidence: 99%

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters

Barr

Auro

Sam-Soon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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181

186

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“…The first step consisted in the generation of a set of contigs using as many reads as possible from 104 oceanic viromes, including 74 epipelagic and 16 mesopelagic samples from the Tara Oceans expedition 6 , and 1 mesopelagic and 13 bathypelagic from the Malaspina expedition 7 . This set of contigs was generated through an iterative cross-assembly 15 (using MOCAT 54 The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/053090 doi: bioRxiv preprint first posted online May.…”

Section: Contigs Assemblymentioning

confidence: 99%

“…Beyond better sample coverage, analytical approaches including cross-assembly 15 and genome binning 16 make the GOV dataset a much improved genomic representation of the sampled viruses. From 1,380,834 contigs generated, which recruited 67% of the reads, we identified 15,280 viral populations (Fig.…”

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confidence: 99%

“…The characterization of new viral-encoded AMGs, their viral carriers, possible impacted hosts, and biogeographical patterns revealed that viral manipulation of cellular processes involves much more than photosynthesis and carbon metabolism [25][26][27][28] , to also now include nitrogen and sulfur cycling throughout the epipelagic ocean. These advances are foundational for interpretation of new (meta)genomic datasets and selection of relevant experimental systems to develop, and, together with myriad experimental, informatic and theoretical advances already occurring 5,15,[42][43][44] , will accelerate the field towards understanding and predicting the roles and global impacts of viruses in nature. …”

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confidence: 99%

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Ecogenomics and potential biogeochemical impacts of globally abundant ocean viruses

Roux

Brum

Dutilh

et al. 2016

Nature

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689

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Tara Oceans CoordinatorsInternational audienceOcean microbes drive biogeochemical cycling on a global scale. However, this cycling is constrained by viruses that affect community composition, metabolic activity, and evolutionary trajectories. Owing to challenges with the sampling and cultivation of viruses, genome-level viral diversity remains poorly described and grossly understudied, with less than 1% of observed surface-ocean viruses known. Here we assemble complete genomes and large genomic fragments from both surface- and deep-ocean viruses sampled during the Tara Oceans and Malaspina research expeditions, and analyse the resulting ‘global ocean virome’ dataset to present a global map of abundant, double-stranded DNA viruses complete with genomic and ecological contexts. A total of 15,222 epipelagic and mesopelagic viral populations were identified, comprising 867 viral clusters (defined as approximately genus-level groups. This roughly triples the number of known ocean viral populations and doubles the number of candidate bacterial and archaeal virus genera, providing a near-complete sampling of epipelagic communities at both the population and viral-cluster level. We found that 38 of the 867 viral clusters were locally or globally abundant, together accounting for nearly half of the viral populations in any global ocean virome sample. While two-thirds of these clusters represent newly described viruses lacking any cultivated representative, most could be computationally linked to dominant, ecologically relevant microbial hosts. Moreover, we identified 243 viral-encoded auxiliary metabolic genes, of which only 95 were previously known. Deeper analyses of four of these auxiliary metabolic genes (dsrC, soxYZ, P-II (also known as glnB) and amoC) revealed that abundant viruses may directly manipulate sulfur and nitrogen cycling throughout the epipelagic ocean. This viral catalog and functional analyses provide a necessary foundation for the meaningful integration of viruses into ecosystem models where they act as key players in nutrient cycling and trophic networks

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“…1D). The lower coverage of novel contigs may have kept them hidden from previous analyses, and only by pooling many samples together were these sequences found (22). Biases in read coverage across the bacterial contigs may also be used to estimate their growth dynamics (23).…”

Section: Significancementioning

confidence: 99%

Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA

Kowarsky

Camunas-Soler

Kertesz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

161

141

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Blood circulates throughout the human body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analyzing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.

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A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes

Cited by 688 publications

References 69 publications

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters

Ecogenomics and potential biogeochemical impacts of globally abundant ocean viruses

Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA

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