In vivo negative regulation of SARS-CoV-2 receptor, ACE2, by interferons and its genetic control

Abstract

Background: Angiotensin I converting enzyme 2 (ACE2) is a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and differences in its expression may affect susceptibility to infection. Methods: We performed a genome-wide expression quantitative trait loci (eQTL) analysis using hepatitis C virus-infected liver tissue from 190 individuals. Results: We discovered that polymorphism in a type III interferon gene (IFNL4), which eliminates IFN-λ4 production, is associated with a two-fold increase in ACE2 RNA expression. Conversely, among genes negatively correlated with ACE2 expression, IFN-signalling pathways were highly enriched and ACE2 was downregulated after IFN-α treatment. Negative correlation was also found in the gastrointestinal tract where inflammation driven IFN-stimulated genes were negatively correlated with ACE2 expression and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of ACE2 across tissue and species. Conclusions: We conclude that ACE2 is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of IFNL4 gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions.

Distribution of Interferon Lambda 4 Single Nucleotide Polymorphism rs11322783 Genotypes in Patients with COVID-19

“…However, data remains conflicting; indeed, ISGs expression is not influenced by the presence of rs11322783 ∆G allele in HIV-1 infected patients [28]. More recently, Azim Ansari et al found that expression of Angiotensin-converting enzyme 2 (ACE2), the functional receptor for SARS-CoV-2 entry into host target cells, is negatively correlated with IFNL4 production [29]. Remarkably, ACE2 transcripts' level (all isoforms) in vivo were correlated with those of ISG15, a marker of type I and III IFNs' activation in patients suffering from respiratory diseases not caused by SARS-CoV-2 [30].…”