SARS-CoV-2 Viral Entry-Related Gene Expression Changes in Response to Cigarette and Glucocorticoid Exposures

Abstract

Rationale: Cigarette smoking has been associated with worse COVID-19 outcomes, while inhaled corticosteroids (ICS) use may be protective against COVID-19. Previous studies have suggested that gene expression levels of key cellular mediators of SARS-CoV-2 infectivity, such as ACE2 and TMPRSS2, are increased in response to cigarette exposure and decreased with glucocorticoids. We sought to determine whether the SARS-CoV-2 entry factor genes ACE2, TMPRSS2 and FURIN had changed expression levels according to publicly available cigarette-, e-cigarette- and glucocorticoid-related transcriptomic datasets of various human cell types. Methods: Thirty-eight transcriptomic datasets related to cigarette and e-cigarette smoking and glucocorticoid response were obtained from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/), including 18 studies related to cigarette and e-cigarette smoking involving 7 airway cell types and 20 studies related to glucocorticoid response involving 11 cell types. RAVED (https://github.com/HimesGroup/raved) was used to analyze each dataset. For genes of interest, which included housekeeping (ATCB, RPL19), positive smoking controls (CYP1A1, CYP1B1) and positive glucocorticoid controls (FKBP5, TSC22D3), nominal p-values and transcriptomic-level false-discovery rate adjusted q-values were obtained. Results: When comparing cigarette smokers versus non-smokers, ACE2 expression levels were significantly increased in small airway epithelia (SAE) and TMPRSS2 expression levels were increased in trachea (q-value <0.05) [Figure 1A]. None of the genes had consistent expression changes in other airway cell types (large airway epithelia (LAE), bronchial epithelia (BE), nasal epithelia (NE), alveolar macrophages, and buccal mucosa) derived from smokers or in in vitro models where cells were exposed to cigarette or e-cigarette smoke [Figure 1A]. Expression levels of FURIN were higher in macrophages and two airway smooth muscle (ASM) studies when exposed to glucocorticoids, but otherwise, ACE2, TMPRSS2 and FURIN were generally unchanged with glucocorticoid exposure in vitro or in asthma patients treated with ICS versus placebo [Figure 1B]. Conclusion: Potential mechanisms linking cigarette smoking to worse COVID-19 outcomes or use of ICS to improved COVID-19 outcomes are unlikely to result from direct gene expression changes to SARS-CoV-2 viral entry genes.