STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters
Hendrik Jan Thibaut,
Suzanne JF Kaptein,
Carolien De Keyzer,
Johan Van Weyenbergh,
Dominique Van Looveren,
Dorien De Vlieger,
Tina Van Buyten,
Marc Van Ranst,
Koen Van Laere,
Greetje Vande Velde,
Posted 24 Apr 2020
bioRxiv DOI: 10.1101/2020.04.23.056838
Posted 24 Apr 2020
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. ### Competing Interest Statement D.D.V., B.S., and X.S. are named as inventors on US patent application no. 62/988,610, entitled 'Coronavirus Binders'. D.D.V., B.S., X.S., and N.C. are named as inventors on US patent application no. 62/991,408, entitled 'SARS-CoV-2 Virus Binders'.
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