Spatiotemporal and demographic patterns of SARS-CoV-2 entry gene expression in a Lebanese cohort

SARS-CoV-2 infection relies on host entry factors, including ACE2, TMPRSS2, FURIN, and CTSL, which are expressed in the nasal epithelium. Characterizing variations in their expression according to demographic factors and infection stage can offer valuable insights into differential susceptibility and disease progression.

The aim was to evaluate the baseline nasopharyngeal expression of SARS-CoV-2 host entry genes in a healthy Lebanese population, stratified by age, sex, and smoking status. We also investigated their dynamic regulation throughout the course of mild COVID-19 infection.

We assessed nasopharyngeal expression of ACE2, TMPRSS2, FURIN, and CTSL in 173 COVID-19-negative individuals stratified by age, sex, and smoking. In 84 mild COVID-19 cases, a longitudinal design was applied to evaluate gene expression at four infection stages using RT-qPCR and promoter analysis.

Baseline expression of ACE2, FURIN, and CTSL decreased significantly with age, especially after adolescence, while TMPRSS2 showed a biphasic pattern. Females exhibited higher expression of ACE2, FURIN, and CTSL than males; smokers showed a trend toward upregulation without statistical significance. During infection, ACE2, TMPRSS2, and FURIN showed a bell-shaped expression pattern-upregulated in early infection, followed by downregulation during late infection and return to baseline post-infection. CTSL expression remained unchanged. Promoter analysis identified binding sites for immune- and hormone-regulated transcription factors (IRFs, STATs, and ESRs) explaining the observed expression differences.

Entry gene expression differs across age, sex, and infection stage; elevated baseline levels in children and females may promote early immune activation and protection, highlighting their complex role in COVID-19 pathogenesis.