Virus adaptation to heparan sulfate comes with capsid stability tradeoff

  1. Han Kang Tee  Is a corresponding author
  2. Simon Crouzet
  3. Arunima Muliyil
  4. Gregory Mathez
  5. Valeria Cagno
  6. Matteo Dal Peraro
  7. Aleksandar Antanasijevic
  8. Sophie Clément
  9. Caroline Tapparel  Is a corresponding author
  1. University of Geneva, Switzerland
  2. École Polytechnique Fédérale de Lausanne, Switzerland

Abstract

Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as model and demonstrated that unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. We experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. We then extended these findings to another HS-dependent strain. In summary, our data indicate that acquisition of capsid mutations conferring affinity for HS come together with decreased capsid stability and allow EV-A71 to enter the cell via a pH-independent pathway. This pH-independent entry mechanism boosts viral replication in cell lines but may prove deleterious in vivo, especially for enteric viruses crossing the acidic gastric environment before reaching their primary replication site, the intestine. Our study thus provides new insight into the mechanisms underlying the in vivo attenuation of HS-binding EV-A71 strains. Not only are these viruses hindered in tissues rich in HS due to viral trapping, as generally accepted, but our research reveals that their diminished capsid stability further contributes to attenuation in vivo. This underscores the complex relationship between HS-binding, capsid stability, and viral fitness, where increased replication in cell lines coincides with attenuation in harsh in vivo environments like the gastrointestinal tract.

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Article and author information

Author details

  1. Han Kang Tee

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    For correspondence
    han.tee@unige.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8975-0945
  2. Simon Crouzet

    Interschool Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Arunima Muliyil

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Gregory Mathez

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4453-7649
  5. Valeria Cagno

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5597-334X
  6. Matteo Dal Peraro

    Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Aleksandar Antanasijevic

    Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9452-8954
  8. Sophie Clément

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Caroline Tapparel

    Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    For correspondence
    caroline.tapparel@unige.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0411-6567

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_184777)

  • Valeria Cagno

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

Copyright

© 2024, Tee et al.

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

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  1. Han Kang Tee
  2. Simon Crouzet
  3. Arunima Muliyil
  4. Gregory Mathez
  5. Valeria Cagno
  6. Matteo Dal Peraro
  7. Aleksandar Antanasijevic
  8. Sophie Clément
  9. Caroline Tapparel
(2024)
Virus adaptation to heparan sulfate comes with capsid stability tradeoff
eLife 13:e98441.
https://doi.org/10.7554/eLife.98441

Share this article

https://doi.org/10.7554/eLife.98441

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