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
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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.

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