MetaHiC phage-bacteria infection network reveals active cycling phages of the healthy human gut

Abstract

Bacteriophages play important roles in regulating the intestinal human microbiota composition, dynamics and homeostasis, and characterizing their bacterial hosts is needed to understand their impact. We applied a metagenomic Hi-C approach on 10 healthy human gut samples to unveil a large infection network encompassing more than 6,000 interactions bridging a metagenomic assembled genomes (MAGs) and a phage sequence, allowing to study in situ phage-host ratio. Whereas three-quarter of these sequences likely correspond to dormant prophages, 5% exhibit a much higher coverage than their associated MAG, representing potentially actively replicating phages. We detected 17 sequences of members of the crAss-like phage family, whose hosts diversity remained until recently relatively elusive. For each of them, a unique bacterial host was identified, all belonging to different genus of Bacteroidetes. Therefore, metaHiC deciphers infection network of microbial population with a high-specificity paving the way to dynamic analysis of mobile genetic elements in complex ecosystems.

Data availability

Sequence data (raw reads, assemblies) have been deposited in the NCBI Sequence Read Archive under the BioProject number PRJNA627086.Code and additional data on MAGs, Bins, Contigs and Phages can be found at the following address https://github.com/mmarbout/HGP-Hi-C.

The following data sets were generated

Article and author information

Author details

  1. Martial Marbouty

    Département Génomes et Génétique, Groupe Régulation Spatiale des Génomes, Institut Pasteur, Paris, France
    For correspondence
    martial.marbouty@pasteur.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Agnès Thierry

    Département Génomes et Génétique, Groupe Régulation Spatiale des Génomes, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Gaël A Millot

    Bioinformatics and Biostatistics Hub, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Romain Koszul

    Département Génomes et Génétique, Groupe Régulation Spatiale des Génomes, Institut Pasteur, Paris, France
    For correspondence
    romain.koszul@pasteur.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3086-1173

Funding

European Research Council (771813)

  • Romain Koszul

Agence Nationale pour la Recherche (ANR-16-JPEC-0003-05)

  • Romain Koszul

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Breck A Duerkop, University of Colorado School of Medicine

Ethics

Human subjects: The work involved feces samples of healthy human individuals, stored in the Institut Pasteur biobanque (library). This research receives the ethical agreement n{degree sign}N18 from Institut Pasteur (ICAReB), and through this process we dont need informed consent from the individual donors.

Version history

  1. Received: July 1, 2020
  2. Accepted: February 20, 2021
  3. Accepted Manuscript published: February 26, 2021 (version 1)
  4. Version of Record published: March 16, 2021 (version 2)

Copyright

© 2021, Marbouty et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,223
    views
  • 621
    downloads
  • 57
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Martial Marbouty
  2. Agnès Thierry
  3. Gaël A Millot
  4. Romain Koszul
(2021)
MetaHiC phage-bacteria infection network reveals active cycling phages of the healthy human gut
eLife 10:e60608.
https://doi.org/10.7554/eLife.60608

Share this article

https://doi.org/10.7554/eLife.60608

Further reading

    1. Microbiology and Infectious Disease
    Guoqi Li, Xiaohong Cao ... Shihua Wang
    Research Article

    The target of rapamycin (TOR) signaling pathway is highly conserved and plays a crucial role in diverse biological processes in eukaryotes. Despite its significance, the underlying mechanism of the TOR pathway in Aspergillus flavus remains elusive. In this study, we comprehensively analyzed the TOR signaling pathway in A. flavus by identifying and characterizing nine genes that encode distinct components of this pathway. The FK506-binding protein Fkbp3 and its lysine succinylation are important for aflatoxin production and rapamycin resistance. The TorA kinase plays a pivotal role in the regulation of growth, spore production, aflatoxin biosynthesis, and responses to rapamycin and cell membrane stress. As a significant downstream effector molecule of the TorA kinase, the Sch9 kinase regulates aflatoxin B1 (AFB1) synthesis, osmotic and calcium stress response in A. flavus, and this regulation is mediated through its S_TKc, S_TK_X domains, and the ATP-binding site at K340. We also showed that the Sch9 kinase may have a regulatory impact on the high osmolarity glycerol (HOG) signaling pathway. TapA and TipA, the other downstream components of the TorA kinase, play a significant role in regulating cell wall stress response in A. flavus. Moreover, the members of the TapA-phosphatase complexes, SitA and Ppg1, are important for various biological processes in A. flavus, including vegetative growth, sclerotia formation, AFB1 biosynthesis, and pathogenicity. We also demonstrated that SitA and Ppg1 are involved in regulating lipid droplets (LDs) biogenesis and cell wall integrity (CWI) signaling pathways. In addition, another phosphatase complex, Nem1/Spo7, plays critical roles in hyphal development, conidiation, aflatoxin production, and LDs biogenesis. Collectively, our study has provided important insight into the regulatory network of the TOR signaling pathway and has elucidated the underlying molecular mechanisms of aflatoxin biosynthesis in A. flavus.

    1. Microbiology and Infectious Disease
    Brian G Vassallo, Noemie Scheidel ... Dennis H Kim
    Research Article

    The microbiota is a key determinant of the physiology and immunity of animal hosts. The factors governing the transmissibility of viruses between susceptible hosts are incompletely understood. Bacteria serve as food for Caenorhabditis elegans and represent an integral part of the natural environment of C. elegans. We determined the effects of bacteria isolated with C. elegans from its natural environment on the transmission of Orsay virus in C. elegans using quantitative virus transmission and host susceptibility assays. We observed that Ochrobactrum species promoted Orsay virus transmission, whereas Pseudomonas lurida MYb11 attenuated virus transmission relative to the standard laboratory bacterial food Escherichia coli OP50. We found that pathogenic Pseudomonas aeruginosa strains PA01 and PA14 further attenuated virus transmission. We determined that the amount of Orsay virus required to infect 50% of a C. elegans population on P. lurida MYb11 compared with Ochrobactrum vermis MYb71 was dramatically increased, over three orders of magnitude. Host susceptibility was attenuated even further in the presence of P. aeruginosa PA14. Genetic analysis of the determinants of P. aeruginosa required for attenuation of C. elegans susceptibility to Orsay virus infection revealed a role for regulators of quorum sensing. Our data suggest that distinct constituents of the C. elegans microbiota and potential pathogens can have widely divergent effects on Orsay virus transmission, such that associated bacteria can effectively determine host susceptibility versus resistance to viral infection. Our study provides quantitative evidence for a critical role for tripartite host-virus-bacteria interactions in determining the transmissibility of viruses among susceptible hosts.