STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

Robbert Boudewijns1,2,3, Hendrik Jan Thibaut4,5,6, Suzanne J F Kaptein1,3, Rong Li7, Valentijn Vergote1,8,9, Laura Seldeslachts10, Johan Van Weyenbergh8, Carolien De Keyzer1,2,3, Lindsey Bervoets1,3, Sapna Sharma1,2,3, Laurens Liesenborghs1,2,3, Ji Ma1,2,3, Sander Jansen1,2,3, Dominique Van Looveren1,3,11, Thomas Vercruysse1,3,11, Xinyu Wang1,2,3, Dirk Jochmans1,2,3, Erik Martens12, Kenny Roose13,14, Dorien De Vlieger13,14, Bert Schepens13,14, Tina Van Buyten1,3, Sofie Jacobs1,3, Yanan Liu7, Joan Martí-Carreras8,9, Bert Vanmechelen8,9, Tony Wawina-Bokalanga8,9, Leen Delang1,3, Joana Rocha-Pereira1,3, Lotte Coelmont1,2,3, Winston Chiu1,3, Pieter Leyssen1,3, Elisabeth Heylen1,3, Dominique Schols1, Lanjiao Wang1,3, Lila Close8,15, Jelle Matthijnssens8,15, Marc Van Ranst8,16,17,18, Veerle Compernolle19,20, Georg Schramm21,22, Koen Van Laere21,22, Xavier Saelens13,14, Nico Callewaert13,14, Ghislain Opdenakker12, Piet Maes8,9, Birgit Weynand23,24, Christopher Cawthorne21, Greetje Vande Velde10, Zhongde Wang7, Johan Neyts25,26,27, Kai Dallmeier28,29,30

  1. Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium.
  2. Molecular Vaccinology and Vaccine Discovery Group, Leuven, Belgium.
  3. GVN, Global Virus Network, Baltimore, MD, USA.
  4. Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium. hendrikjan.thibaut@kuleuven.be.
  5. GVN, Global Virus Network, Baltimore, MD, USA. hendrikjan.thibaut@kuleuven.be.
  6. Translational Platform Virology and Chemotherapy, Leuven, Belgium. hendrikjan.thibaut@kuleuven.be.
  7. Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, 84322-4815, USA.
  8. Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium.
  9. Zoonotic Infectious Diseases Unit, Leuven, Belgium.
  10. KU Leuven Department of Imaging and Pathology, Biomedical MRI and MoSAIC, 3000, Leuven, Belgium.
  11. Translational Platform Virology and Chemotherapy, Leuven, Belgium.
  12. Immunity and Inflammation Research Group, Immunobiology Unit, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium.
  13. VIB-UGent Center for Medical Biotechnology, VIB, 9052, Ghent, Belgium.
  14. Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium.
  15. Laboratory of Viral Metagenomics, Leuven, Belgium.
  16. KU Leuven Department of Laboratory Medicine, University Hospitals Leuven, 3000, Leuven, Belgium.
  17. National Reference Center for Respiratory Pathogens and Enteroviruses, 3000, Leuven, Belgium.
  18. Leuven University Vaccinology Center (LUVAC), 3000, Leuven, Belgium.
  19. Blood Service, Belgian Red Cross Flanders, Mechelen, Belgium.
  20. Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  21. KU Leuven Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging and MoSAIC, 3000, Leuven, Belgium.
  22. Division of Nuclear Medicine, University Hospitals Leuven, 3000, Leuven, Belgium.
  23. KU Leuven Department of Imaging and Pathology, Translational Cell and Tissue Research, 3000, Leuven, Belgium.
  24. Division of Translational Cell and Tissue Research, Leuven, Belgium.
  25. Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium. johan.neyts@kuleuven.be.
  26. Molecular Vaccinology and Vaccine Discovery Group, Leuven, Belgium. johan.neyts@kuleuven.be.
  27. GVN, Global Virus Network, Baltimore, MD, USA. johan.neyts@kuleuven.be.
  28. Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium. kai.dallmeier@kuleuven.be.
  29. Molecular Vaccinology and Vaccine Discovery Group, Leuven, Belgium. kai.dallmeier@kuleuven.be.
  30. GVN, Global Virus Network, Baltimore, MD, USA. kai.dallmeier@kuleuven.be.

Abstract

Emergence of SARS-CoV-2 causing COVID-19 has resulted in 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 Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as 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. 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.

Presented By Robbert Boudewijns | ORCID iD

COVID-19, MicrobiologyNicholas Liao2020-11 (Nov)