{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:58:42Z","timestamp":1788998322762,"version":"build-2803163510"},"reference-count":81,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Innate Immun"],"published-print":{"date-parts":[[2023]]},"abstract":"<jats:p>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin (Ang)-converting enzyme 2 (ACE2). Altering ACE2 levels may affect entry of SARS-CoV-2 and recovery from COVID-19. Decreased cell surface density of ACE2 leads to increased local levels of Ang II and may contribute to mortality resulting from acute lung injury and fibrosis during COVID-19. Studies published early during the COVID-19 pandemic reported that people with cystic fibrosis (PwCF) had milder symptoms, compared to people without CF. This finding was attributed to elevated ACE2 levels and\/or treatment with the high efficiency CFTR modulators. Subsequent studies did not confirm these findings reporting variable effects of &lt;i&gt;CFTR&lt;\/i&gt; gene mutations on ACE2 levels. Transforming growth factor (TGF)-\u03b2 signaling is essential during SARS-CoV-2 infection and dominates the chronic immune response in severe COVID-19, leading to pulmonary fibrosis. TGF-\u03b21 is a gene modifier associated with more severe lung disease in PwCF but its effects on the COVID-19 course in PwCF is unknown. To understand whether TGF-\u03b21 affects ACE2 levels in the airway, we examined miRNAs and their gene targets affecting SARS-CoV-2 pathogenesis in response to TGF-\u03b21. Small RNAseq and micro(mi)RNA profiling identified pathways uniquely affected by TGF-\u03b21, including those associated with SARS-CoV-2 invasion, replication, and the host immune responses. TGF-\u03b21 inhibited ACE2 expression by miR-136-3p and miR-369-5p mediated mechanism in CF and non-CF bronchial epithelial cells. ACE2 levels were higher in two bronchial epithelial cell models expressing the most common CF-causing mutation in &lt;i&gt;CFTR&lt;\/i&gt; gene &lt;i&gt;F508del&lt;\/i&gt;, compared to controls without the mutation. After TGF-\u03b21 treatment, ACE2 protein levels were still higher in CF, compared to non-CF cells. TGF-\u03b21 prevented the modulator-mediated rescue of F508del-CFTR function while the modulators did not prevent the TGF-\u03b21 inhibition of ACE2 levels. Finally, TGF-\u03b21 reduced the interaction between ACE2 and the recombinant spike RBD by lowering ACE2 levels and its binding to RBD. Our data demonstrate novel mechanism whereby TGF-\u03b21 inhibition of ACE2 in CF and non-CF bronchial epithelial cells may modulate SARS-CoV-2 pathogenicity and COVID-19 severity. By reducing ACE2 levels, TGF-\u03b21 may decrease entry of SARS-CoV-2 into the host cells while hindering the recovery from COVID-19 due to loss of the anti-inflammatory and regenerative effects of ACE2. The above outcomes may be modulated by other, miRNA-mediated effects exerted by TGF-\u03b21 on the host immune responses, leading to a complex and yet incompletely understood circuitry. <\/jats:p>","DOI":"10.1159\/000533606","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T21:01:15Z","timestamp":1692046875000},"page":"629-646","source":"Crossref","is-referenced-by-count":14,"title":["TGF-\u03b21 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis"],"prefix":"10.1159","volume":"15","author":[{"given":"Ewelina D.","family":"Hejenkowska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilay","family":"Mitash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua 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