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JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic.One Sentence SummaryInhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.
- Subjects :
- 0303 health sciences
Down syndrome
education.field_of_study
Innate immune system
business.industry
animal diseases
medicine.medical_treatment
Population
Stimulation
medicine.disease
3. Good health
03 medical and health sciences
0302 clinical medicine
Cytokine
Immune system
Immunology
medicine
Chromosome 21
education
business
Cytokine storm
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....119b48f08f20efc291a698cfa26f7758
- Full Text :
- https://doi.org/10.1101/2020.04.07.024455