In vivo negative regulation of SARS-CoV-2 receptor, ACE2, by interferons and its genetic control
Ansari MA., Marchi E., Ramamurthy N., Aschenbrenner D., Morgan S., Hackstein C-P., Lin S-K., Bowden R., Sharma E., Pedergnana V., Venkateswaran S., Kugathasan S., Mo A., Gibson G., Cooke GS., McLauchlan J., Baillie JK., Teichmann S., Mentzer A., Knight J., Todd JA., Hinks T., Barnes EJ., Uhlig H., Klenerman P.
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.