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

Boudewijns, R.; Thibaut, H. J.; Kaptein, S. J. F.; Li, R.; Vergote, V.; Seldeslachts, L.; De Keyzer, C.; Sharma, S.; Jansen, S.; Van Weyenbergh, J.; Ma, J.; Martens, E.; Bervoets, L.; Van Buyten, T.; Jacobs, S.; Liu, Y.; Marti-Carreras, J.; Vanmechelen, B.; Wawina-Bokalanga, T.; Delang, L.; Rocha-Pereira, J.; Coelmont, L.; Chiu, W.; Leyssen, P.; Heylen, E.; Schols, D.; Wang, L.; Close, L.; Matthijnssens, J.; Van Ranst, M.; Schramm, G.; Van Laere, K.; Opdenakker, G.; Maes, P.; Weynand, B.; Cawthorne, C.; Vande Velde, G.; Wang, Z.; Neyts, J.; Dallmeier, K.

doi:10.1101/2020.04.23.056838

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bioRxiv · 10.1101/2020.04.23.056838

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

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Abstract

Introductory paragraphSince 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.

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Boudewijns, R., Thibaut, H. J., Kaptein, S. J. F., Li, R., Vergote, V., Seldeslachts, L., De Keyzer, C., Sharma, S., Jansen, S., Van Weyenbergh, J., Ma, J., Martens, E., Bervoets, L., Van Buyten, T., Jacobs, S., Liu, Y., Marti-Carreras, J., Vanmechelen, B., Wawina-Bokalanga, T., Delang, L., Rocha-Pereira, J., Coelmont, L., Chiu, W., Leyssen, P., Heylen, E., Schols, D., Wang, L., Close, L., Matthijnssens, J., Van Ranst, M., Schramm, G., Van Laere, K., Opdenakker, G., Maes, P., Weynand, B., Cawthorne, C., Vande Velde, G., Wang, Z., Neyts, J., Dallmeier, K.. 2020-04-24. STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters. https://doi.org/10.1101/2020.04.23.056838

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