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JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
Sci Adv. 2021 01; 7(1)SA

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.

Authors+Show Affiliations

Department of Surgery and Cancer, Imperial College, London, UK. j.stebbing@imperial.ac.uk volker.lauschke@ki.se.Department of Rheumatology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.BenevolentAI, Maple Street, London, UK.Department of Surgery and Cancer, Imperial College, London, UK.Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, Pisa, University of Pisa, Italy.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.Department of Internal Medicine, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, Pisa, University of Pisa, Italy.Department of Pharmaceutical Medicine, Misericordia Hospital, Grosseto, Italy.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.Department of Pharmaceutical Medicine, Misericordia Hospital, Grosseto, Italy.Department of Medicine, Misericordia Hospital, Grosseto, Italy.Department of Radiology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Medicine, Misericordia Hospital, Grosseto, Italy.Department of Rheumatology, Hospital of Prato, Prato, Italy.Department of Internal Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Hospital Network ASL Toscana Centro, Toscana, Italy.Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases-IRCCS, Rome, Italy.University of Singapore, Infectious Diseases Programme, Immunology Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore and Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.Karolinska Institutet, Department of Laboratory Medicine, Unit of Clinical Microbiology, and SE-17177, Stockholm, Sweden.Department of Hematology, School of Medicine, University of Ioannina, Ioannina, Greece.Department of Rheumatology, Hospital of Prato, Prato, Italy.Department of Economics and Finance, University of Rome Tor Vergata, Rome Italy.RCSB Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.RCSB Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.Departments of Anesthesia, Medicine, and Physiology, University of Toronto, Toronto, ON, Canada.Virology Unit, Department of Translational Research, University of Pisa, Pisa, Italy.The Angiogenesis Foundation, Cambridge, MA, USA.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Statistics, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Pneumology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.Oxford Nanoimaging, Oxford, UK.Oxford Nanoimaging, Oxford, UK.Oxford Nanoimaging, Oxford, UK.Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC, Canada.Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.Karolinska Institutet, Department of Laboratory Medicine, Unit of Clinical Microbiology, and SE-17177, Stockholm, Sweden. National Veterinary Institute, Uppsala, Sweden.Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. j.stebbing@imperial.ac.uk volker.lauschke@ki.se.

Pub Type(s)

Journal Article
Multicenter Study
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

33187978

Citation

Stebbing, Justin, et al. "JAK Inhibition Reduces SARS-CoV-2 Liver Infectivity and Modulates Inflammatory Responses to Reduce Morbidity and Mortality." Science Advances, vol. 7, no. 1, 2021.
Stebbing J, Sánchez Nievas G, Falcone M, et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. 2021;7(1).
Stebbing, J., Sánchez Nievas, G., 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., Avendaño Céspedes, A., De Marco, S., Carrozzi, L., Lena, F., Sánchez-Jurado, P. M., ... 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). https://doi.org/10.1126/sciadv.abe4724
Stebbing J, et al. JAK Inhibition Reduces SARS-CoV-2 Liver Infectivity and Modulates Inflammatory Responses to Reduce Morbidity and Mortality. Sci Adv. 2021;7(1) PubMed PMID: 33187978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. AU - Stebbing,Justin, AU - Sánchez Nievas,Ginés, AU - Falcone,Marco, AU - Youhanna,Sonia, AU - Richardson,Peter, AU - Ottaviani,Silvia, AU - Shen,Joanne X, AU - Sommerauer,Christian, AU - Tiseo,Giusy, AU - Ghiadoni,Lorenzo, AU - Virdis,Agostino, AU - Monzani,Fabio, AU - Rizos,Luis Romero, AU - Forfori,Francesco, AU - Avendaño Céspedes,Almudena, AU - De Marco,Salvatore, AU - Carrozzi,Laura, AU - Lena,Fabio, AU - Sánchez-Jurado,Pedro Manuel, AU - Lacerenza,Leonardo Gianluca, AU - Cesira,Nencioni, AU - Caldevilla Bernardo,David, AU - Perrella,Antonio, AU - Niccoli,Laura, AU - Méndez,Lourdes Sáez, AU - Matarrese,Daniela, AU - Goletti,Delia, AU - Tan,Yee-Joo, AU - Monteil,Vanessa, AU - Dranitsaris,George, AU - Cantini,Fabrizio, AU - Farcomeni,Alessio, AU - Dutta,Shuchismita, AU - Burley,Stephen K, AU - Zhang,Haibo, AU - Pistello,Mauro, AU - Li,William, AU - Romero,Marta Mas, AU - Andrés Pretel,Fernando, AU - Simón-Talero,Rafaela Sánchez, AU - García-Molina,Rafael, AU - Kutter,Claudia, AU - Felce,James H, AU - Nizami,Zehra F, AU - Miklosi,Andras G, AU - Penninger,Josef M, AU - Menichetti,Francesco, AU - Mirazimi,Ali, AU - Abizanda,Pedro, AU - Lauschke,Volker M, Y1 - 2021/01/01/ PY - 2020/08/24/received PY - 2020/10/28/accepted PY - 2020/11/15/pubmed PY - 2021/2/17/medline PY - 2020/11/14/entrez JF - Science advances JO - Sci Adv VL - 7 IS - 1 N2 - 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. SN - 2375-2548 UR - https://www.unboundmedicine.com/medline/citation/33187978/JAK_inhibition_reduces_SARS_CoV_2_liver_infectivity_and_modulates_inflammatory_responses_to_reduce_morbidity_and_mortality_ L2 - https://doi.org/10.1126/sciadv.abe4724 DB - PRIME DP - Unbound Medicine ER -