STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters

Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and prospected 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. In wild-type hamsters, SARS-CoV-2 infection triggers bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. We further assess SARS-CoV-2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Finally, we identify an exuberant innate response as key player in immune pathogenesis, in which STAT2 signaling plays a double-edged role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results endorse hamsters as pre-clinical model to rationalize and assess the therapeutic benefit of new antivirals or immune modulators for the treatment of COVID-19 patients.