1. Microbiology and Infectious Disease
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Type III CRISPR-Cas systems can provide redundancy to counteract viral escape from type I systems

  1. Sukrit Silas
  2. Patricia Lucas-Elio
  3. Simon A Jackson
  4. Alejandra Aroca-Crevillén
  5. Loren L Hansen
  6. Peter C Fineran
  7. Andrew Z Fire  Is a corresponding author
  8. Antonio Sánchez-Amat  Is a corresponding author
  1. Stanford University, United States
  2. Universidad de Murcia, Spain
  3. University of Otago, New Zealand
  4. Stanford University School of Medicine, United States
Research Article
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Cite this article as: eLife 2017;6:e27601 doi: 10.7554/eLife.27601

Abstract

CRISPR-Cas-mediated defense utilizes information stored as spacers in CRISPR arrays to defend against genetic invaders. We define the mode of target interference and role in antiviral defense for two CRISPR-Cas systems in Marinomonas mediterranea. One system (type I-F) targets DNA. A second system (type III-B) is broadly capable of acquiring spacers in either orientation from RNA and DNA, and exhibits transcription-dependent DNA interference. Examining resistance to phages isolated from Mediterranean seagrass meadows, we found that the type III-B machinery co-opts type I-F CRISPR-RNAs. Sequencing and infectivity assessments of related bacterial and phage strains suggests an "arms race" in which phage escape from the type I-F system can be overcome through use of type I-F spacers by a horizontally-acquired type III-B system. We propose that the phage-host arms race can drive selection for horizontal uptake and maintenance of promiscuous type III interference modules that supplement existing host type I CRISPR-Cas systems.

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The following previously published data sets were used

Article and author information

Author details

  1. Sukrit Silas

    Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Patricia Lucas-Elio

    Genetics and Microbiology, Universidad de Murcia, Murcia, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7182-1189
  3. Simon A Jackson

    Microbiology and Immunology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4512-3093
  4. Alejandra Aroca-Crevillén

    Genetics and Microbiology, Universidad de Murcia, Murcia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Loren L Hansen

    Pathology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter C Fineran

    Microbiology & Immunology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4639-6704
  7. Andrew Z Fire

    Pathology and Genetics, Stanford University School of Medicine, Stanford, United States
    For correspondence
    afire@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6217-8312
  8. Antonio Sánchez-Amat

    Genetics and Microbiology, Universidad de Murcia, Murcia, Spain
    For correspondence
    antonio@um.es
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01-GM37706)

  • Andrew Z Fire

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

Reviewing Editor

  1. Blake Wiedenheft, Montana State University, United States

Publication history

  1. Received: April 8, 2017
  2. Accepted: August 7, 2017
  3. Accepted Manuscript published: August 17, 2017 (version 1)
  4. Version of Record published: August 30, 2017 (version 2)
  5. Version of Record updated: March 2, 2018 (version 3)
  6. Version of Record updated: April 4, 2018 (version 4)

Copyright

© 2017, Silas 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.

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Further reading

    1. Medicine
    2. Microbiology and Infectious Disease
    Alexander O Pasternak et al.
    Research Article Updated

    Background:

    It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).

    Methods:

    CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART.

    Results:

    In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.

    Conclusions:

    All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

    Funding:

    This work was supported by ZonMw (09120011910035) and FP7 Health (305522).