SARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation

Abstract

As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis could be considered a comorbidity for coronavirus disease 2019. Instead, current clinical evidence seems to be heading in the opposite direction. To clarify whether host factors expressed by the Cystic Fibrosis epithelia may influence coronavirus disease 2019 progression, here we describe the expression of SARS-CoV-2 receptors in primary airway epithelial cells. We show that angiotensin converting enzyme 2 (ACE2) expression and localization are regulated by Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Consistently, our results indicate that dysfunctional CFTR channels alter susceptibility to SARS-CoV-2 infection, resulting in reduced viral entry and replication in Cystic Fibrosis cells. Depending on the pattern of ACE2 expression, the SARS-CoV-2 spike (S) protein induced high levels of Interleukin 6 in healthy donor-derived primary airway epithelial cells, but a very weak response in primary Cystic Fibrosis cells. Collectively, these data support that Cystic Fibrosis condition may be at least partially protecting from SARS-CoV-2 infection.

Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS‐CoV‐2 infection and COVID‐19 disease severity

“…Using two independent protocols at two virology laboratories, we observed donor‐to‐donor differences, but comparable replication levels of SARS‐CoV‐2 in CF versus non‐CF monolayers under conditions studied here (Figure 1C,D). This result contrasts findings from others 80 …”

“…This result is similar to a previous report in which Bezzerri et al showed ACE2 was deficient in CF primary airway epithelia as judged by quantitative immunofluorescence. The same report indicated decreased SARS‐CoV‐2 replication and diminished IL6 expression in the CF samples 80 . TMPRSS2 RNA expression was variable (Figure 1A), but (unlike ACE2) demonstrated moderate correlation with SARS‐CoV‐2 replication (Figure 1B, R 2 = .76), compatible with importance of secreted proteases during the viral infectious cycle 30,81 .…”

“…The same report indicated decreased SARS-CoV-2 replication and diminished IL6 expression in the CF samples. 80 TMPRSS2 RNA expression was variable (Figure 1A), but (unlike ACE2) demonstrated moderate correlation with SARS-CoV-2 replication (Figure 1B, R 2 = .76), compatible with importance of secreted proteases during the viral infectious cycle. 30,81 Protease/anti-protease imbalance is well established in CF airways in vivo, [82][83][84][85][86][87][88][89][90][91] and the possibility that clinical features of CF lung disease related to protease activity might influence SARS-CoV-2 infection has been suggested previously.…”

“…This result contrasts findings from others. 80 F I G U R E 1 SARS-CoV-2-related features of primary human airway (bronchial) epithelium (hBEC) from three non-CF individuals or three patients with CF. Human primary cells were prepared as differentiated monolayers at air-liquid interface for each data point.…”

Angiotensin-converting enzyme 2: virus accomplice or host defender?

“…For example, Bezzerri et al found that downregulation of ACE2 leads to impaired replication of SARS-CoV-2. [73] Tu et al found that ACE2 localized in the nucleus is closely related to the replication of SARS-CoV-2. [74] In addition, John et al reported that the expression of ACE2 not Journal of Bio-X Research only determines whether an individual is infected but also in turn regulates the host's response and outcome.…”