JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells

Abstract

SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

Regulation of IFNα-induced expression of the short ACE2 isoform by ULK1

“…For instance, a recent study found that fludarabine, which inhibits STAT1, among other proteins, was able to dampen type I IFN-induced expression of ACE2 ( Xiu et al, 2021 ). Another study reported that IFNs mainly activate transcription of dACE2 and, to a lower degree, ACE2 in human airway epithelial cells and this was mitigated by the JAK inhibitors ruxolitinib and baricitinib ( Lee et al, 2021 ). Here, we identified ULK1 as a key and essential component of the IFN-ULK1-dACE2 axis, suggesting ULK1 as a potential drug target to block this cascade.…”

Oral anti-COVID-19 drugs that were recently evaluated by FDA or EMA: a review

“…It has a good safety and efficacy profile, despite some concerns [52][53][54][55]. Baricitinib is able to modulate the cytokine storm through the JAK-STAT pathway [56][57][58][59][60][61][62]. Artificial Intelligence algorithms suggested its utility in treating COVID-19 [63][64][65][66] and it has been proved effective in animal models [67,68].…”

Genetic immune response and antibody repertoire of heterologous ChAdOx1-BNT162b2 vaccination in a Korean cohort

“…CXCL10 (IP-10) expression is rapidly activated following vaccination and viral infections and it has been described as a biomarker associated with COVID-19 severity [16][17][18] . Its regulation by IFN-g is mediated by the JAK-STAT signaling pathway 19 .…”