Negative regulation of ACE2 by interferons in vivo and its genetic control

The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally. ACE2 is a receptor for SARS-CoV-2 and differences in expression may affect susceptibility to COVID-19. Using HCV-infected liver tissue from 195 individuals, we discovered that among genes negatively correlated with ACE2, interferon signalling pathways were highly enriched and observed down-regulation of ACE2 after interferon-alpha treatment. Negative correlation was also found in the gastrointestinal tract and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of ACE2 across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda (IFNL) region are associated with ACE2 expression. Increased ACE2 expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in the IFNL region may impact not only antiviral responses but also ACE2 with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.