Regulation of the Expression of SARS-CoV-2 Receptor Angiotensin-Converting Enzyme 2 in Nasal Mucosa

Abstract

Background Coronavirus disease 2019 (COVID-19) has caused a global pandemic. Higher expression of the virus receptor angiotensin-converting enzyme 2 (ACE2) in the nasal mucosa may be associated with high transmissibility and asymptomatic infection. In COVID-19, the elucidation of the determinants of ACE2 expression at nasal tissue level is crucial. The development of strategies to downregulate ACE2 expression in nasal epithelial cells might reduce transmission and be useful as a novel therapeutic approach. Objective To verify ACE2 expression in the nasal mucosa of patients with seasonal allergic rhinitis induced by Japanese cedar pollen (SAR-JCP) and chronic rhinosinusitis with nasal polyp (CRSwNP) and to examine the effects of short-chain fatty acids (SCFAs) on ACE2 expression in airway epithelial cells. Methods We assessed ACE2 expression in the nasal mucosa of control subjects, patients with SAR-JCP, and those with CRSwNP using real-time polymerase chain reaction. We also quantified ACE2 gene expression in cultured airway epithelial cells. Results Although ACE2 expression was greatly increased in a few patients with SAR-JCP during the Japanese cedar pollen season, mean levels were not significantly increased. ACE2 mRNA expression was significantly decreased in nasal polyp tissue from patients with chronic rhinosinusitis compared with the expression in that from control subjects. SCFAs generated by gastrointestinal microbiota significantly reduced resting ACE2 expression in cultured airway epithelial cells. SCFAs also significantly suppressed the dsRNA-dependent upregulation of ACE2 expression in airway epithelial cells. Conclusion Inflammatory endotype affects ACE2 expression in the nasal mucosa and influences susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In particular, type 2 inflammation could downregulate ACE2 expression in the nasal mucosa and reduces susceptibility to SARS-CoV-2 in patients with CRSwNP. Although in vivo experiments are required, administration of SCFAs to the nasal cavity might be worthy of consideration as a preventative or therapeutic strategy for the early-stage COVID-19.

Recent developments in the immunopathology of COVID-19

“…Reduced ACE2 expression was observed in bronchial epithelial cells from patients with concomitant AR and allergic asthma 47 , suggesting a potential protective effect of atopy against susceptibility and severity of COVID-19. The expression of ACE2 in nasal polyp tissues of patients with CRS was lower than that of healthy controls 52 . The expression of ACE2 and TMPRSS2 was also lower in the olfactory mucosa of patients with chronic rhinosinusitis with nasal polys (CRSwNP) compared to healthy controls, and the protein expression of ACE2 was negatively correlated with eosinophils numbers in olfactory mucosa 53 .…”

Nasopharyngeal Angiotensin Converting Enzyme 2 (ACE2) Expression as a Risk-Factor for SARS-CoV-2 Transmission in Concurrent Hospital Associated Outbreaks

“…High nasopharyngeal ACE2 expression has been associated with long term inhaled corticosteroid use and exposure to fine particulate matter PM 2.5 . Below average, low nasopharyngeal ACE2 transcription is associated with type 2 inflammation mediated by the cytokines IL-4, IL-5, and IL-13 [54,55]. Therefore, individuals with asthma or allergic rhinitis may have lower upper airway ACE2 expression than those that do not.…”

Chronic Rhinosinusitis and COVID-19

“…Interestingly, given the lower risk for COVID-19 among CRS patients, a differential expression of ACE2 has been hypothesized. Along this line, a reduced expression of ACE2 messenger RNA (mRNA) and protein was observed in CRSwNP respiratory airway epithelial cells, including nasal polyps, 86,[89][90][91][92][93] and in olfactory mucosa 94 compared with noneosinophilic CRS and control subjects. Similar findings were reported in asthmatic patients.…”