Negative regulation of ACE2 by interferons in vivo and its genetic control
Ansari MA., Marchi E., Ramamurthy N., Aschenbrenner D., Hackstein C-P., Lin S-K., Bowden R., Sharma E., Pedergnana V., Venkateswaran S., Kugathasan S., Mo A., Gibson G., Cooke G., McLauchlan J., Barnes E., Baillie JK., Teichmann S., Mentzer A., Todd J., Knight J., Uhlig H., Klenerman P.
<jats:title>Abstract</jats:title><jats:p>The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally. <jats:italic>ACE2</jats:italic> 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 <jats:italic>ACE2</jats:italic>, interferon signalling pathways were highly enriched and observed down-regulation of <jats:italic>ACE2</jats:italic> 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 <jats:italic>ACE2</jats:italic> across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda (<jats:italic>IFNL</jats:italic>) region are associated with <jats:italic>ACE2</jats:italic> expression. Increased <jats:italic>ACE2</jats:italic> expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in the <jats:italic>IFNL</jats:italic> region may impact not only antiviral responses but also <jats:italic>ACE2</jats:italic> with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.</jats:p>