In patients with cystic fibrosis (CF), destructive CF transmembrane conductance regulator (CFTR) channels alter susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, resulting in decreased viral entry and replication in CF cells. The findings were published in Nature Communications.

The researchers sought to elucidate whether host factors expressed by the CF epithelia may impact the progression of coronavirus disease 2019 (COVID-19). They hypothesized that although behavioral factors such as the improved ability and motivation to self-isolate may be linked to the reduced number of critical COVID-19 cases reported among patients with CF, some specific host factors associated with the disease may impact an individual’s susceptibility to SARS-CoV-2 infection.

It is well known that the genome of SARS-CoV-2 encodes 28 proteins, including 4 structural proteins: (1) spike (S), (2) membrane, (3) envelope, and (4) nucleocapsid. The S glycoprotein of SARS-CoV-2 is responsible for viral entry through binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Once the S protein has bound to the ACE2 receptor, it is processed by a number of proteases, which promote the priming of the S protein and the fusion of viral and cellular membranes.

To determine whether CFTR expression affects ACE2 expression, the investigators applied gene-editing approaches to modulate CFTR expression in different bronchial epithelial cell models.

The findings unambiguously demonstrated that CFTR expression was associated with ACE2 expression—in particular, CFTR-deficient short hairpin RNA cells displayed reductions of nearly 18% and 19% of ACE2 levels compared with parental human lung adenocarcinoma Calu-3 cells and mock-transfected cells, respectively.

Depending on the pattern of ACE2 expression observed, the SARS-CoV-2 S protein induced high levels of interleukin-6 in healthy, donor-derived primary airway epithelial cells but a very weak response in primary CF cells.

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Additionally, the researchers demonstrated that the CFTR channel and ACE2 receptor colocalize in bronchial epithelial cells. To confirm the role played by CFTR in the SARS-CoV-2 life cycle, they utilized 2 complementary strategies, which included the use of pharmacologic inhibition of CFTR function and a micro RNA-based approach to specifically downregulate CFTR synthesis with the use of Calu-3 cells.

“This work provides further insights into the regulation of expression and localization of ACE2 receptor in relation to CFTR channel expression and function,” the authors wrote. “This issue is of substantial interest for unraveling additional aspects in the pathogenesis of SARS-CoV-2 infection.”

They concluded that “collectively, these data support that cystic fibrosis condition may be at least partially protecting from SARS-CoV-2 infection.”

Reference

Bezzerri V, Gentili V, Api M, et al. SARS-CoV-2 viral entry and replication is impaired in cystic fibrosis airways due to ACE2 downregulation. Nat Commun. 2023;14(1):132. doi:10.1038/s41467-023-35862-0