TGF-& beta;1 inhibition of ACE2 mediated by miRNA uncovers novel mechanism of SARS-CoV-2 pathogenesis.

SARS-CoV-2 utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin-converting enzyme 2 (ACE2). Decreased cell surface density of ACE2 contributes to mortality during COVID-19. Studies published early during the pandemic reported that people with cystic fibrosis (PwCF) treated with the high efficiency CFTR modulators ETI (elexacaftor-tezacaftor-ivacaftor) had higher ACE2 levels and milder COVID-19 symptoms, compared to people without CF. Subsequent studies did not confirm these findings. TGF-& beta;1 gene polymorphisms associated with higher TGF-& beta;1 levels, present in approximately 40% of CF patients, lead to more severe CF lung disease. To understand whether TGF-& beta;1 modulates COVID-19 severity by affecting ACE2 levels in the airway, we performed small RNAseq and microRNA profiling and identified pathways uniquely affected by TGF-& beta;1, including those associated with SARS-CoV-2 invasion. TGF-& beta;1 inhibited ACE2 expression by miR-136-3p and miR-369-5p. ACE2 levels were higher in CF bronchial epithelial cell models. ETI did not prevent TGF-& beta;1 inhibition of ACE2. Finally, TGF-& beta;1 reduced the interaction between ACE2 and RBD by lowering ACE2 levels and its binding to RBD. Our data demonstrate novel mechanism whereby TGF-& beta;1 inhibition of ACE2 in CF and non-CF bronchial epithelia may modulate SARS-CoV-2 pathogenicity and COVID-19 severity. By reducing ACE2 levels, TGF-& beta;1 may decrease entry of SARS-CoV-2 into host cells while hindering recovery from COVID-19 due to loss of anti-inflammatory effects of ACE2.