Your browser doesn't support javascript.
JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
Stebbing, Justin; Sánchez Nievas, Ginés; Falcone, Marco; Youhanna, Sonia; Richardson, Peter; Ottaviani, Silvia; Shen, Joanne X; Sommerauer, Christian; Tiseo, Giusy; Ghiadoni, Lorenzo; Virdis, Agostino; Monzani, Fabio; Rizos, Luis Romero; Forfori, Francesco; Avendaño Céspedes, Almudena; De Marco, Salvatore; Carrozzi, Laura; Lena, Fabio; Sánchez-Jurado, Pedro Manuel; Lacerenza, Leonardo Gianluca; Cesira, Nencioni; Caldevilla Bernardo, David; Perrella, Antonio; Niccoli, Laura; Méndez, Lourdes Sáez; Matarrese, Daniela; Goletti, Delia; Tan, Yee-Joo; Monteil, Vanessa; Dranitsaris, George; Cantini, Fabrizio; Farcomeni, Alessio; Dutta, Shuchismita; Burley, Stephen K; Zhang, Haibo; Pistello, Mauro; Li, William; Romero, Marta Mas; Andrés Pretel, Fernando; Simón-Talero, Rafaela Sánchez; García-Molina, Rafael; Kutter, Claudia; Felce, James H; Nizami, Zehra F; Miklosi, Andras G; Penninger, Josef M; Menichetti, Francesco; Mirazimi, Ali; Abizanda, Pedro; Lauschke, Volker M.
  • Stebbing J; Department of Surgery and Cancer, Imperial College, London, UK. j.stebbing@imperial.ac.uk volker.lauschke@ki.se.
  • Sánchez Nievas G; Department of Rheumatology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Falcone M; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Youhanna S; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • Richardson P; BenevolentAI, Maple Street, London, UK.
  • Ottaviani S; Department of Surgery and Cancer, Imperial College, London, UK.
  • Shen JX; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • Sommerauer C; Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
  • Tiseo G; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Ghiadoni L; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Virdis A; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Monzani F; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Rizos LR; Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Forfori F; CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.
  • Avendaño Céspedes A; Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, Pisa, University of Pisa, Italy.
  • De Marco S; Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Carrozzi L; CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.
  • Lena F; Department of Internal Medicine, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
  • Sánchez-Jurado PM; Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, Pisa, University of Pisa, Italy.
  • Lacerenza LG; Department of Pharmaceutical Medicine, Misericordia Hospital, Grosseto, Italy.
  • Cesira N; Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Caldevilla Bernardo D; CIBERFES, Ministerio de Economía y Competitividad, Madrid, Spain.
  • Perrella A; Department of Pharmaceutical Medicine, Misericordia Hospital, Grosseto, Italy.
  • Niccoli L; Department of Medicine, Misericordia Hospital, Grosseto, Italy.
  • Méndez LS; Department of Radiology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Matarrese D; Department of Medicine, Misericordia Hospital, Grosseto, Italy.
  • Goletti D; Department of Rheumatology, Hospital of Prato, Prato, Italy.
  • Tan YJ; Department of Internal Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Monteil V; Hospital Network ASL Toscana Centro, Toscana, Italy.
  • Dranitsaris G; Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases-IRCCS, Rome, Italy.
  • Cantini F; 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), Singapo
  • Farcomeni A; Karolinska Institutet, Department of Laboratory Medicine, Unit of Clinical Microbiology, and SE-17177, Stockholm, Sweden.
  • Dutta S; Department of Hematology, School of Medicine, University of Ioannina, Ioannina, Greece.
  • Burley SK; Department of Rheumatology, Hospital of Prato, Prato, Italy.
  • Zhang H; Department of Economics and Finance, University of Rome Tor Vergata, Rome Italy.
  • Pistello M; RCSB Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
  • Li W; RCSB Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
  • Romero MM; Departments of Anesthesia, Medicine, and Physiology, University of Toronto, Toronto, ON, Canada.
  • Andrés Pretel F; Virology Unit, Department of Translational Research, University of Pisa, Pisa, Italy.
  • Simón-Talero RS; The Angiogenesis Foundation, Cambridge, MA, USA.
  • García-Molina R; Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Kutter C; Department of Statistics, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Felce JH; Department of Pneumology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Nizami ZF; Department of Geriatric Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
  • Miklosi AG; Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
  • Penninger JM; Oxford Nanoimaging, Oxford, UK.
  • Menichetti F; Oxford Nanoimaging, Oxford, UK.
  • Mirazimi A; Oxford Nanoimaging, Oxford, UK.
  • Abizanda P; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
  • Lauschke VM; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC, Canada.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432
Semantic information from SemMedBD (by NLM)
1. Liver LOCATION_OF COVID-19
Subject
Liver
Predicate
LOCATION_OF
Object
COVID-19
2. COVID-19 AFFECTS Inflammatory Response
Subject
COVID-19
Predicate
AFFECTS
Object
Inflammatory Response
3. Pneumonia PROCESS_OF Patients
Subject
Pneumonia
Predicate
PROCESS_OF
Object
Patients
4. IFNA2 protei STIMULATES C1422064|59272
Subject
IFNA2 protei
Predicate
STIMULATES
Object
C1422064|59272
5. baricitinib INHIBITS Platelet Activation
Subject
baricitinib
Predicate
INHIBITS
Object
Platelet Activation
6. Malaise PROCESS_OF geriatric patients
Subject
Malaise
Predicate
PROCESS_OF
Object
geriatric patients
7. Cytokine Storm PROCESS_OF geriatric patients
Subject
Cytokine Storm
Predicate
PROCESS_OF
Object
geriatric patients
8. Liver LOCATION_OF COVID-19
Subject
Liver
Predicate
LOCATION_OF
Object
COVID-19
9. COVID-19 AFFECTS Inflammatory Response
Subject
COVID-19
Predicate
AFFECTS
Object
Inflammatory Response
10. Pneumonia PROCESS_OF Patients
Subject
Pneumonia
Predicate
PROCESS_OF
Object
Patients
11. IFNA2 protein, human|IFNA2 STIMULATES ACE2 gene|ACE2
Subject
IFNA2 protein, human|IFNA2
Predicate
STIMULATES
Object
ACE2 gene|ACE2
12. baricitinib INHIBITS Platelet Activation
Subject
baricitinib
Predicate
INHIBITS
Object
Platelet Activation
13. Malaise PROCESS_OF geriatric patients
Subject
Malaise
Predicate
PROCESS_OF
Object
geriatric patients
14. Cytokine Storm PROCESS_OF geriatric patients
Subject
Cytokine Storm
Predicate
PROCESS_OF
Object
geriatric patients
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Purines / Pyrazoles / Sulfonamides / Azetidines / Enzyme Inhibitors / Janus Kinases / SARS-CoV-2 / COVID-19 / Liver Type of study: Controlled clinical trial / Randomized controlled trials Topics: Traditional medicine Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Year: 2021 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Purines / Pyrazoles / Sulfonamides / Azetidines / Enzyme Inhibitors / Janus Kinases / SARS-CoV-2 / COVID-19 / Liver Type of study: Controlled clinical trial / Randomized controlled trials Topics: Traditional medicine Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Year: 2021 Document Type: Article