1. Microbiology and Infectious Disease
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Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state

  1. Miri Shnayder
  2. Aharon Nachshon
  3. Batsheva Rozman
  4. Biana Bernshtein
  5. Michael Lavi
  6. Noam Fein
  7. Emma Poole
  8. Selmir Avdic
  9. Emily Blyth
  10. David Gottlieb
  11. Allison Abendroth
  12. Barry Slobedman
  13. John Sinclair
  14. Noam Stern-Ginossar  Is a corresponding author
  15. Michal Schwartz  Is a corresponding author
  1. Weizmann Institute of Science, Israel
  2. University of Cambridge, United Kingdom
  3. Sydney Cellular Therapies Laboratory, Australia
  4. University of Sydney, Australia
Research Article
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Cite this article as: eLife 2020;9:e52168 doi: 10.7554/eLife.52168

Abstract

Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq analysis to characterize latency in monocytes and hematopoietic stem and progenitor cells (HSPCs). In monocytes, we identify host cell surface markers that enable enrichment of latent cells harboring higher viral transcript levels, which can reactivate more efficiently, and are characterized by reduced intrinsic immune response that is important for viral gene expression. Significantly, in latent HSPCs, viral transcripts could be detected only in monocyte progenitors and were also associated with reduced immune-response. Overall, our work indicates that regardless of the developmental stage in which HCMV infects, HCMV drives hematopoietic cells towards a weaker immune-responsive monocyte state and that this anergic-like state is crucial for the virus ability to express its transcripts and to eventually reactivate.

Data availability

Sequencing data have been deposited in GEO under accession code GSE138838

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Miri Shnayder

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Aharon Nachshon

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Batsheva Rozman

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Biana Bernshtein

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Lavi

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Noam Fein

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Emma Poole

    Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3904-6121
  8. Selmir Avdic

    Sydney Cellular Therapies Laboratory, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Emily Blyth

    Sydney Cellular Therapies Laboratory, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. David Gottlieb

    Sydney Cellular Therapies Laboratory, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Allison Abendroth

    Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Barry Slobedman

    Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9431-6094
  13. John Sinclair

    Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Noam Stern-Ginossar

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    noam.stern-ginossar@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3583-5932
  15. Michal Schwartz

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    michalsc@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5442-0201

Funding

Infect-ERA (TANKACY)

  • Noam Stern-Ginossar

H2020 European Research Council (starting grant (StG-2014-638142))

  • Noam Stern-Ginossar

Cambridge NIHR BRC Cell Phenotyping Hub

  • John Sinclair

British Medical Research Council (G0701279)

  • John Sinclair

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

Ethics

Human subjects: All fresh peripheral blood samples were obtained after approval of protocols bythe Weizmann Institutional Review Board (IRB application 92-1). Informed written consent was obtained from all volunteers, and all experiments were carried out in accordance with the approved guidelines. The study using HSCT recipient samples was approved by the Human Research Ethics Committee of the University of Sydney and the Western Sydney Local Health District. Informed consent was obtained from all study participants prior to enrolment in accordance with the Declaration of Helsinki.

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: September 24, 2019
  2. Accepted: January 21, 2020
  3. Accepted Manuscript published: January 22, 2020 (version 1)
  4. Version of Record published: February 24, 2020 (version 2)
  5. Version of Record updated: July 16, 2020 (version 3)

Copyright

© 2020, Shnayder 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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