JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

Stebbing, J., Nievas, G.S., Falcone, M., Youhanna, S., Richardson, P., Ottaviani, S. ORCID: 0000-0002-8830-9947, Shen, J.X., Sommerauer, C., Tiseo, G., Ghiadoni, L., Virdis, A., Monzani, F., Rizos, L.R., Forfori, F., Céspedes, A.A., de Marco, S., Carrozzi, L., Lena, F., Sánchez-Jurado, P.M., Lacerenza, L.G., Cesira, N., Bernardo, D.C., Perrella, A., Niccoli, L., Méndez, L.S., Matarrese, D., Goletti, D., Tan, Y.-J., Monteil, V., Dranitsaris, G., Cantini, F., Farcomeni, A., Dutta, S., Burley, S.K., Zhang, H., Pistello, M., Li, W., Romero, M.M., Pretel, F.A., Simón-Talero, R.S., García-Molina, R., Kutter, C., Felce, J.H., Nizami, Z.F., Miklosi, A.G., Penninger, J.M., Menichetti, F., Mirazimi, A., Abizanda, P. and Lauschke, V.M., 2021. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Science Advances, 7 (1): eabe4724. ISSN 2375-2548

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Abstract

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Item Type:	Journal article
Publication Title:	Science Advances
Creators:	Stebbing, J., Nievas, G.S., Falcone, M., Youhanna, S., Richardson, P., Ottaviani, S., Shen, J.X., Sommerauer, C., Tiseo, G., Ghiadoni, L., Virdis, A., Monzani, F., Rizos, L.R., Forfori, F., Céspedes, A.A., de Marco, S., Carrozzi, L., Lena, F., Sánchez-Jurado, P.M., Lacerenza, L.G., Cesira, N., Bernardo, D.C., Perrella, A., Niccoli, L., Méndez, L.S., Matarrese, D., Goletti, D., Tan, Y.-J., Monteil, V., Dranitsaris, G., Cantini, F., Farcomeni, A., Dutta, S., Burley, S.K., Zhang, H., Pistello, M., Li, W., Romero, M.M., Pretel, F.A., Simón-Talero, R.S., García-Molina, R., Kutter, C., Felce, J.H., Nizami, Z.F., Miklosi, A.G., Penninger, J.M., Menichetti, F., Mirazimi, A., Abizanda, P. and Lauschke, V.M.
Publisher:	American Association for the Advancement of Science
Date:	1 January 2021
Volume:	7
Number:	1
ISSN:	2375-2548
Identifiers:	Number Type 10.1126/sciadv.abe4724 DOI 1537676 Other
Rights:	Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	14 Apr 2022 09:03
Last Modified:	14 Apr 2022 09:03
URI:	https://irep.ntu.ac.uk/id/eprint/46130

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