JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy

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.

Data, Reagents, Assays and Merits of Proteomics for SARS-CoV-2 Research and Testing

“…Unfortunately, global and protein-specific surface glycosylation profiling is still challenging but could become an important future avenue to understand better how complex glycan patterns both of the virus as well as host cells determine the tropism of SARS-CoV-2. A rapidly rising number of reports on SARS-CoV-2 implicate intracellular phosphorylation events in a plethora of pathways from growth factor signaling to interferons and interleukins, HIF1A/mTOR signaling, PIKFYVE kinase inhibition, and JAK1 signaling ( 39 , 64 , 65 , 66 , 67 , 68 , 69 ), many of which are implicated in innate immunity. The full extent of phosphorylation regulation (or other PTMs for that matter) by SARS-CoV-2 remains to be elucidated.…”

COVID-19 and children with Down syndrome: is there any real reason to worry? Two case reports with severe course

“…For that reason, the IFN response, which is crucial for escalating antiviral responses, besides driving and amplifying the cytokine storm, is vigorous in people with DS [1,8].…”

Down Syndrome patients with COVID-19 pneumonia: A high-risk category for unfavourable outcome

“…Studies have showed in DS the occurrence of an interferonopathyc signature with a dysregulation of IFN-inducible cytokines causing a chronic inflammation state Sullivan et al, 2016 , Sullivan et al, 2017 , and a widespread hypersensitivity to IFN stimulation across the human immune system [Araya et al, 2019] . Recently, in an animal model carrying triplication of these IFN receptors, activation of toll-like receptors and consequent induction of the IFN antiviral response, lead to a cytokine storm with a worsening of liver pathology and rapid death [Tuttle et al, 2020] ( Fig. 1 ).…”