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

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

doi:10.1038/s41467-020-19684-y

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

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

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Abstract

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.

Original language	English
Article number	5838
Journal	Nature Communications
Volume	11
Issue number	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-020-19684-y
Publication status	Published - 2020

Keywords

Animals
Betacoronavirus/pathogenicity
COVID-19
Coronavirus Infections/immunology
Cricetinae
Disease Models, Animal
Immunity, Innate
Interferon Type I/genetics
Lung/pathology
Mice
Pandemics
Pneumonia, Viral/immunology
SARS-CoV-2
STAT2 Transcription Factor/genetics
Signal Transduction
Virus Replication

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2020ncom5838Final published version, 1.82 MBLicence: CC BY

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Boudewijns, R., Thibaut, H. J., Kaptein, S. J. F., Li, R., Vergote, V., Seldeslachts, L., Van Weyenbergh, J., De Keyzer, C., Bervoets, L., Sharma, S., Liesenborghs, L., Ma, J., Jansen, S., Van Looveren, D., Vercruysse, T., Wang, X., Jochmans, D., Martens, E., Roose, K., ... Dallmeier, K. (2020). STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nature Communications, 11(1), Article 5838. https://doi.org/10.1038/s41467-020-19684-y

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

abstract = "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.",

keywords = "Animals, Betacoronavirus/pathogenicity, COVID-19, Coronavirus Infections/immunology, Cricetinae, Disease Models, Animal, Immunity, Innate, Interferon Type I/genetics, Lung/pathology, Mice, Pandemics, Pneumonia, Viral/immunology, SARS-CoV-2, STAT2 Transcription Factor/genetics, Signal Transduction, Virus Replication",

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

note = "FTX; DOAJ; (CC BY 4.0)",

year = "2020",

doi = "10.1038/s41467-020-19684-y",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Boudewijns, R, Thibaut, HJ, Kaptein, SJF, Li, R, Vergote, V, Seldeslachts, L, Van Weyenbergh, J, De Keyzer, C, Bervoets, L, Sharma, S, Liesenborghs, L, Ma, J, Jansen, S, Van Looveren, D, Vercruysse, T, Wang, X, Jochmans, D, Martens, E, Roose, K, De Vlieger, D, Schepens, B, Van Buyten, T, Jacobs, S, Liu, Y, Martí-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, Compernolle, V, Schramm, G, Van Laere, K, Saelens, X, Callewaert, N, Opdenakker, G, Maes, P, Weynand, B, Cawthorne, C, Vande Velde, G, Wang, Z, Neyts, J & Dallmeier, K 2020, 'STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters', Nature Communications, vol. 11, no. 1, 5838. https://doi.org/10.1038/s41467-020-19684-y

TY - JOUR

T1 - STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

AU - Boudewijns, Robbert

AU - Thibaut, Hendrik Jan

AU - Kaptein, Suzanne J F

AU - Li, Rong

AU - Vergote, Valentijn

AU - Seldeslachts, Laura

AU - Van Weyenbergh, Johan

AU - De Keyzer, Carolien

AU - Bervoets, Lindsey

AU - Sharma, Sapna

AU - Liesenborghs, Laurens

AU - Ma, Ji

AU - Jansen, Sander

AU - Van Looveren, Dominique

AU - Vercruysse, Thomas

AU - Wang, Xinyu

AU - Jochmans, Dirk

AU - Martens, Erik

AU - Roose, Kenny

AU - De Vlieger, Dorien

AU - Schepens, Bert

AU - Van Buyten, Tina

AU - Jacobs, Sofie

AU - Liu, Yanan

AU - Martí-Carreras, Joan

AU - Vanmechelen, Bert

AU - Wawina-Bokalanga, Tony

AU - Delang, Leen

AU - Rocha-Pereira, Joana

AU - Coelmont, Lotte

AU - Chiu, Winston

AU - Leyssen, Pieter

AU - Heylen, Elisabeth

AU - Schols, Dominique

AU - Wang, Lanjiao

AU - Close, Lila

AU - Matthijnssens, Jelle

AU - Van Ranst, Marc

AU - Compernolle, Veerle

AU - Schramm, Georg

AU - Van Laere, Koen

AU - Saelens, Xavier

AU - Callewaert, Nico

AU - Opdenakker, Ghislain

AU - Maes, Piet

AU - Weynand, Birgit

AU - Cawthorne, Christopher

AU - Vande Velde, Greetje

AU - Wang, Zhongde

AU - Neyts, Johan

AU - Dallmeier, Kai

N1 - FTX; DOAJ; (CC BY 4.0)

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Animals

KW - Betacoronavirus/pathogenicity

KW - COVID-19

KW - Coronavirus Infections/immunology

KW - Cricetinae

KW - Disease Models, Animal

KW - Immunity, Innate

KW - Interferon Type I/genetics

KW - Lung/pathology

KW - Mice

KW - Pandemics

KW - Pneumonia, Viral/immunology

KW - SARS-CoV-2

KW - STAT2 Transcription Factor/genetics

KW - Signal Transduction

KW - Virus Replication

U2 - 10.1038/s41467-020-19684-y

DO - 10.1038/s41467-020-19684-y

M3 - A1: Web of Science-article

C2 - 33203860

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5838

ER -

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

Abstract

Keywords

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