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

• Published in: Nature communications Vol. 11; no. 1; p. 5838
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 38/77; 631/250/254; 631/250/255/2514; 631/326/421; 631/326/596/4130; 64/110; 64/60; Animal models; Animals; Betacoronavirus - pathogenicity; Betacoronavirus - physiology; Bronchopneumonia; Computed tomography; Coronavirus Infections - immunology; Coronavirus Infections - metabolism; Coronavirus Infections - pathology; Coronavirus Infections - virology; Coronaviruses; COVID-19; Cricetinae; Disease Models, Animal; Edema; Hamsters; Humanities and Social Sciences; Immune response; Immunity, Innate; Infections; Inflammation; Innate immunity; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Lung - pathology; Lung - virology; Lungs; Mice; Mimicry; multidisciplinary; Pandemics; Pathogenesis; Pneumonia, Viral - immunology; Pneumonia, Viral - metabolism; Pneumonia, Viral - pathology; Pneumonia, Viral - virology; Rodents; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Signaling; Stat2 protein; STAT2 Transcription Factor - genetics; STAT2 Transcription Factor - metabolism; Viral diseases; Virus Replication; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19684-y

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. SARS-CoV-2 infection can result in severe lung inflammation and pathology, but host response remains incompletely understood. Here the authors show in Syrian hamsters that STAT2 signaling restricts systemic virus dissemination but also drives severe lung injury, playing a dual role in SARS-CoV-2 infection.