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

Boudewijns, Robbert; Thibaut, Hendrik Jan; Kaptein, Suzanne J. F.; Li, Rong; Vergote, Valentijn; Seldeslachts, Laura; Van Weyenbergh, Johan; De Keyzer, Carolien; Bervoets, Lindsey; Sharma, Sapna; Liesenborghs, Laurens; Ma, Ji; Jansen, Sander; Van Looveren, Dominique; Vercruysse, Thomas; Wang, Xinyu; Jochmans, Dirk; Martens, Erik; Roose, Kenny; De Vlieger, Dorien; Schepens, Bert; Van Buyten, Tina; Jacobs, Sofie; Liu, Yanan; Martí-Carreras, Joan; Vanmechelen, Bert; Wawina-Bokalanga, Tony; Delang, Leen; Rocha-Pereira, Joana; Coelmont, Lotte; Chiu, Winston; Leyssen, Pieter; Heylen, Elisabeth; Schols, Dominique; Wang, Lanjiao; Close, Lila; Matthijnssens, Jelle; Van Ranst, Marc; Compernolle, Veerle; Schramm, Georg; Van Laere, Koen; Saelens, Xavier; Callewaert, Nico; Opdenakker, Ghislain; Maes, Piet; Weynand, Birgit; Cawthorne, Christopher; Vande Velde, Greetje; Wang, Zhongde; Neyts, Johan; Dallmeier, Kai

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.