SARS-CoV-2 (COVID-19) and cystic fibrosis

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene. Although viral respiratory tract infections are, in general, more severe in patients with CF compared with the general population, a small number of studies indicate that SARS-CoV-2 does not cause a worse infection in CF. This is surprising since comorbidities including preexisting lung disease have been reported to be associated with worse outcomes in SARS-CoV-2 infections. Several recent studies provide insight into why SARS-CoV-2 may not produce more severe outcomes in CF. First, ACE and ACE2, genes that play key roles in SARS-CoV-2 infection, have some variants that are predicted to reduce the severity of SARS-CoV-2 infection. Second, mRNA for ACE2 is elevated and mRNA for TMPRSS2, a serine protease, is decreased in CF airway epithelial cells. Increased ACE2 is predicted to enhance SARS-CoV-2 binding to cells but would increase conversion of angiotensin II, which is proinflammatory, to angiotensin-1-7, which is anti-inflammatory. Thus, increased ACE2 would reduce inflammation and lung damage due to SARS-CoV-2. Moreover, decreased TMPRSS2 would reduce SARS-CoV-2 entry into airway epithelial cells. Second, many CF patients are treated with azithromycin, which suppresses viral infection and lung inflammation and inhibits the activity of furin, a serine protease. Finally, the CF lung contains high levels of serine protease inhibitors including ecotin and SERPINB1, which are predicted to reduce the ability of TMPRSS2 to facilitate SARS-CoV-2 entry into airway epithelial cells. Thus, a variety of factors may mitigate the severity of SARS-CoV-2 in CF.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; cystic fibrosis.

Fig. 1.

Role of angiotensin-converting enzyme (ACE), ACE2, and TMPRSS2 in SARS-CoV-2 lung infection. A: ACE cleaves angiotensin I (ANG I) to angiotensin II (ANG II), which is proinflammatory and causes lung damage. ACE2 processes ANG II to angiotensin-1–7, which is anti-inflammatory. Thus, a decrease in ACE and/or an increase in ACE2 would reduce inflammation and lung damage due to SARS-CoV-2. B: 1) SARS-CoV-2 binds to ACE2. 2) The S protein is cleaved by TMPRSS2 and furin, which facilitates viral entry into cells. 3) Several serine protease inhibitors in the cystic fibrosis (CF) lung, including ecotin and SERP1NR1, and the drugs camostat mesylate and nelfinavir mesylate inhibit TMPRSS2. 4). Azithromycin and chloromethyl ketone inhibit furin. The inhibitors of TMPRSS2 and furin are predicted to reduce SARS-CoV-2 entry into airway epithelial cells.

Fig. 2.

Analysis of published gene array data using ScanGeo (39) to examine the effect of mutations in the CFTR gene on angiotensin-converting enzyme (ACE), ACE2, and TMPRSS2 mRNA. We used ScanGEO (http://scangeo.dartmouth.edu/ScanGEO/) to conduct a meta-analysis of ACE2 and TMPRSS2 genes in human airway epithelial cell microarray data (39). Twenty-three data sets were identified in ScanGEO by selecting genus (Homo) from a pulldown list and entering “airway epithelia” into a text box. Next, ACE, ACE2, and TMPRSS2 were uploaded from a comma-separated value file. Two studies comparing cystic fibrosis (CF) and non-CF [wild type (WT)] airway epithelia were identified by ScanGEO, and statistical differences in gene expression between the CF and non-CF data sets in each study were analyzed by ANOVA using a threshold of P < 0.05, the default setting. Data from these studies were downloaded from ScanGEO, as well as data from an additional RNA-seq data set (89) and 1 other microarray data set (76) and further analyzed in R. ACE2 in the studies by Hampton et al. (26) and Voisin et al. (76) was increased in CF compared with non-CF airway epithelial cells. TMPRSS2 mRNA was decreased in CF vs. non-CF airway epithelial cells (76). However, 1 RNA-seq study on CF and non-CF cells did not identify a difference in ACE2 and TMPRSS2 mRNA levels (89). Our analysis also revealed that ACE mRNA was not differentially expressed in CF cells vs. non-CF airway epithelial cells. There are many possible reasons why mutations in CFTR do not elicit a reproducible effect on ACE2 and TMPRSS2 mRNA levels, including differences in the methods used to assess mRNA levels, differences in the cells examined, and differences in cell culture techniques. Thus, additional studies are needed to examine ACE2 and TMPRSS2 mRNA and protein levels, preferably on freshly isolated CF and non-CF nasal and airway epithelial cells. Each data point in this figure represents a sample. *P < 0.05, **P < 0.01 (Welch’s t test).