Human Cytomegalovirus antagonizes activation of Fcγ receptors by distinct and synergizing modes of IgG manipulation

  1. Philipp Kolb
  2. Katja Hoffmann
  3. Annika Sievert
  4. Henrike Reinhard
  5. Eva Merce-Maldonado
  6. Vu Thuy Khanh Le-Trilling
  7. Anne Halenius
  8. Dominique Gütle
  9. Hartmut Hengel  Is a corresponding author
  1. Albert-Ludwigs-Universität Freiburg, Germany
  2. Heinrich-Heine-University Düsseldorf, Germany
  3. University Hospital Essen, University of Duisburg-Essen, Germany

Abstract

Human Cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (FcγR) mediated immune control mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all pertinent Figures (Figures 1D, 3D, 4C, 5D, 6B, 6C, 6D, Figure 4-figure supplement 1)

Article and author information

Author details

  1. Philipp Kolb

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Katja Hoffmann

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Annika Sievert

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Henrike Reinhard

    Heinrich-Heine-University Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Eva Merce-Maldonado

    Heinrich-Heine-University Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Vu Thuy Khanh Le-Trilling

    Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Anne Halenius

    Institut of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Dominique Gütle

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Hartmut Hengel

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    For correspondence
    hartmut.hengel@uniklinik-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3482-816X

Funding

Deutsche Forschungsgemeinschaft (HE2526/9-1; FOR2830)

  • Hartmut Hengel

Bundesministerium für Bildung und Forschung (031L0090)

  • Hartmut Hengel

Faculty of Medicine, Albert-Ludwigs-University; (EQUIP - Funding for Medical Scientists)

  • Philipp Kolb

Deutsche Forschungsgemeinschaft (HA6035/2-1; FOR2830)

  • Anne Halenius

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

Ethics

Human subjects: Consent of blood donors was approved by the ethical review committee, University of Freiburg, vote 474/18.

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: October 9, 2020
  2. Accepted: March 15, 2021
  3. Accepted Manuscript published: March 16, 2021 (version 1)
  4. Version of Record published: April 12, 2021 (version 2)

Copyright

© 2021, Kolb 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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  1. Philipp Kolb
  2. Katja Hoffmann
  3. Annika Sievert
  4. Henrike Reinhard
  5. Eva Merce-Maldonado
  6. Vu Thuy Khanh Le-Trilling
  7. Anne Halenius
  8. Dominique Gütle
  9. Hartmut Hengel
(2021)
Human Cytomegalovirus antagonizes activation of Fcγ receptors by distinct and synergizing modes of IgG manipulation
eLife 10:e63877.
https://doi.org/10.7554/eLife.63877

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