JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
Sci Adv
; 7(1)2021 01.
Article
in English
| MEDLINE | ID: covidwho-1388432
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.
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:
Cohort study
/
Experimental Studies
/
Observational study
/
Prognostic study
/
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
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