1. Microbiology and Infectious Disease
Download icon

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
  • Cited 6
  • Views 1,989
  • Annotations
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.

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.

Metrics

  • 1,989
    Page views
  • 365
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Ecology
    2. Microbiology and Infectious Disease
    Tjibbe Donker
    Insight

    Moving patients between wards and prescribing high levels of antibiotics increases the spread of bacterial infections that are resistant to treatment in hospitals.

    1. Microbiology and Infectious Disease
    2. Structural Biology and Molecular Biophysics
    James B Eaglesham et al.
    Research Article Updated

    DNA viruses in the family Poxviridae encode poxin enzymes that degrade the immune second messenger 2′3′-cGAMP to inhibit cGAS-STING immunity in mammalian cells. The closest homologs of poxin exist in the genomes of insect viruses suggesting a key mechanism of cGAS-STING evasion may have evolved outside of mammalian biology. Here we use a biochemical and structural approach to discover a broad family of 369 poxins encoded in diverse viral and animal genomes and define a prominent role for 2′3′-cGAMP cleavage in metazoan host-pathogen conflict. Structures of insect poxins reveal unexpected homology to flavivirus proteases and enable identification of functional self-cleaving poxins in RNA-virus polyproteins. Our data suggest widespread 2′3′-cGAMP signaling in insect antiviral immunity and explain how a family of cGAS-STING evasion enzymes evolved from viral proteases through gain of secondary nuclease activity. Poxin acquisition by poxviruses demonstrates the importance of environmental connections in shaping evolution of mammalian pathogens.