STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters

  1. Robbert Boudewijns
  2. Hendrik Jan Thibaut
  3. Suzanne J. F. Kaptein
  4. Rong Li
  5. Valentijn Vergote
  6. Laura Seldeslachts
  7. Carolien De Keyzer
  8. Lindsey Bervoets
  9. Sapna Sharma
  10. Johan Van Weyenbergh
  11. Laurens Liesenborghs
  12. Ji Ma
  13. Sander Jansen
  14. Dominique Van Looveren
  15. Thomas Vercruysse
  16. Dirk Jochmans
  17. Xinyu Wang
  18. Erik Martens
  19. Kenny Roose
  20. Dorien De Vlieger
  21. Bert Schepens
  22. Tina Van Buyten
  23. Sofie Jacobs
  24. Yanan Liu
  25. Joan Martí-Carreras
  26. Bert Vanmechelen
  27. Tony Wawina-Bokalanga
  28. Leen Delang
  29. Joana Rocha-Pereira
  30. Lotte Coelmont
  31. Winston Chiu
  32. Pieter Leyssen
  33. Elisabeth Heylen
  34. Dominique Schols
  35. Lanjiao Wang
  36. Lila Close
  37. Jelle Matthijnssens
  38. Marc Van Ranst
  39. Veerle Compernolle
  40. Georg Schramm
  41. Koen Van Laere
  42. Xavier Saelens
  43. Nico Callewaert
  44. Ghislain Opdenakker
  45. Piet Maes
  46. Birgit Weynand
  47. Christopher Cawthorne
  48. Greetje Vande Velde
  49. Zhongde Wang
  50. Johan Neyts
  51. Kai Dallmeier

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

Article activity feed

  1. Version published to 10.1101/2020.04.23.056838v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.04.23.056838: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: Housing conditions and experimental procedures were approved by the ethical committee of KU Leuven (license P015-2020), following institutional guidelines approved by the Federation of European Laboratory Animal Science Associations (FELASA).
    Consent: Human convalescent serum (HCS) was donated under informed consent (Patient #1).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableSix- to eight-weeks-old female mice and wild-type hamsters were used throughout the
    Cell Line AuthenticationContamination: Prior to inoculation of animals, virus stocks were confirmed to be free of mycoplasma (PlasmoTest, InvivoGen) and other adventitious agents by deep sequencing on a MiSeq platform (Illumina) following an established metagenomics pipeline64,65.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    For maintenance of Calu-3 cells (human airway epithelium, kind gift from Lieve Naesens, KU Leuven, BE), the above medium was supplemented with 10mM HEPES (Gibco).
    Calu-3
    suggested: None
    Infectious virus was isolated by serial passaging on HuH7 and Vero E6 cells (see Fig.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Experimental Models: Organisms/Strains
    SentencesResources
    All other mouse (C57BL/6, Ifnar1-/-, Il28r-/-, BALB/c and SCID) and hamster (STAT2-/- and IL28R-a-/-) strains were bred in-house.
    C57BL/6
    suggested: None
    Il28r-/-
    suggested: None
    BALB/c
    suggested: None
    Ifnar1-/- mouse breeding couples were a generous gift of Dr. Claude Libert, IRC/VIB, University of Ghent, Belgium. Il28r-/- mice [C57B/6N-A Ifnlr1/Wtsi, strain ID: EM:07988] were provided by the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP)61.
    Ifnar1-/-
    suggested: None
    C57B/6N-A Ifnlr1/Wtsi
    suggested: None
    STAT2-/- and IL28R-a-/- hamsters were generated by CRISPR/Cas-mediated gene targeting.
    STAT2-/-
    suggested: None
    Software and Algorithms
    SentencesResources
    SARS-CoV-2 strain BetaCov/Belgium/GHB-03021/2020 (EPI ISL 407976|2020-02-03) recovered from a nasopharyngeal swab taken from a RT-qPCR-confirmed asymptomatic patient returning from Wuhan, China beginning of February 202062 was directly sequenced on a MinION platform (Oxford Nanopore) as described previously63.
    MinION
    suggested: (MinION, RRID:SCR_017985)
    Pathway, GO (Gene Ontology) and transcription factor target enrichment analysis was performed using GSEA (
    GSEA
    suggested: (SeqGSEA, RRID:SCR_005724)
    Principal component analysis, correlation matrices, unsupervised hierarchical clustering (Eucledian distance) were performed using XLSTAT and visualized using MORPHEUS (https://software.broadinstitute.org/morpheus) as described previously20.
    XLSTAT
    suggested: (XLSTAT, RRID:SCR_016299)
    MORPHEUS
    suggested: (Morpheus, RRID:SCR_014975)
    Statistical analysis: GraphPad Prism Version 8 (
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.04.23.056838v1 on bioRxiv