Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

Abstract

SARS-CoV-2 infection continues to pose a significant life threat, especially in patients with comorbidities. It remains unknown, if asthma or allergen- and virus-induced airway inflammation are risk factors or can constitute some forms of protection against COVID-19. ACE2 and other SARS-CoV-2-related host proteins are limiting factors of an infection, expression of which is regulated in a more complex way than previously anticipated. Hence, we studied the expression of ACE2 mRNA and protein isoforms, together with its glycosylation and spatial localization in house dust mite (HDM)-, interleukin-13 (IL-13)- and human rhinovirus (RV)-induced inflammation in the primary human bronchial airway epithelium of healthy subjects and patients with asthma. IL-13 decreased the expression of long ACE2 mRNA and glycosylation of full-length ACE2 protein via alteration of the N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. RV infection increased short ACE2 mRNA, but it did not influence its protein expression. HDM exposure did not affect ACE2 mRNA or protein. IL-13 and RV significantly regulated mRNA, but not protein expression of TMPRSS2 and NRP1. Regulation of ACE2 and other host proteins was similar in healthy and asthmatic epithelium, underlining the lack of intrinsic differences, but rather the dependence on the inflammatory milieu in the airways.

Recent developments in the immunopathology of COVID‐19

“… 53 Another recent study in preprint also demonstrated that IL‐13 decreased the expression of long ACE2 mRNA and reduced glycosylation of full‐length ACE2 protein, leading to reduction in the apical expression of ACE2 on the ciliated airway epithelial cells. 54 These data indicate that the inflammatory milieu may be an important factor affecting the expression of ACE2 and other SARS‐CoV‐2‐relevant receptors, and thus affect the susceptibility and infection. Genetic variation of allergic disease was associated with a lower risk of COVID‐19.…”

“…IL‐13 in combination with mucus was shown to reduce SARS‐CoV‐2 RNA by 90%–97% after inoculation of this virus in cultured human bronchial epithelial cells 53 . Another recent study in preprint also demonstrated that IL‐13 decreased the expression of long ACE2 mRNA and reduced glycosylation of full‐length ACE2 protein, leading to reduction in the apical expression of ACE2 on the ciliated airway epithelial cells 54 . These data indicate that the inflammatory milieu may be an important factor affecting the expression of ACE2 and other SARS‐CoV‐2‐relevant receptors, and thus affect the susceptibility and infection.…”