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.
Highlights
Entry of coronaviruses into susceptible cells depends on the binding of the spike (S) protein to a specific cell-surface protein and subsequent S protein priming by cellular proteases
We conclude that Angiotensin I converting enzyme 2 (ACE2) is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of Interferon Lambda 4 (IFNL4) gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions
To understand the impact of polymorphisms in the IFNL4 gene and other host factors on ACE2 expression in presence of viral infection, we focused on the impact of IFNL4 single nucleotide polymorphisms (SNPs)
Summary
Entry of coronaviruses into susceptible cells depends on the binding of the spike (S) protein to a specific cell-surface protein and subsequent S protein priming by cellular proteases. Similar to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 (COVID-19) virus) employs Angiotensin I converting enzyme 2 (ACE2) as a receptor for cellular entry[1]. Polymorphisms in the host genome could drive differences in ACE2 expression, which may affect susceptibility to SARS-CoV-2 infection and its consequences. 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. 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
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