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Ciliated epithelial cells (CEC; 80% of the nasal epithelium) each contain about 300 cilia that beat in a coordinated fashion, mediating elimination of infectious agents. CEC in the nasal and upper airway mucosa are key targets for SARS-CoV-2.
Wu et al. utilized nasal epithelial organoid cultures to show how SARS-CoV-2 infects nasal mucosa by first attaching to the distal ends of cilia via the angiotensin-converting–enzyme 2 (ACE2) receptor, then crossing the mucous layer and accessing the CEC cell body by using motile cilia as tracks. Although very few epithelial cells are initially infected, SARS-CoV-2 “hijacks” their intracellular machinery, resulting in elongated, branched microvilli that allow viral emergence from the microvilli back into the mucous layer followed by lateral viral spread to infect other cells using mucociliary transport. Treating CECs with a ciliary dynein inhibitor or a transmembrane serine protease 2 (TMPRSS2) inhibitor significantly attenuated viral infection. Interestingly, hydroxychloroquine had no effect on SARS-CoV-2 infection. While depleting cilia blocked SARS-CoV-2 entry independent of ACE2 or TMPRSS2 levels, depleting mucin accelerated viral entry. Omicron variants showed considerably higher efficiency at infecting nasal epithelial cultures, perhaps through greater affinity for ACE2.
Wu C-T et al. SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming. Cell 2022 Dec 2; [e-pub]. (https://doi.org/10.1016/j.cell.2022.11.030)
Comment
SARS-CoV-2 infects ciliated epithelial cells, and not goblet or basal supporting cells. While cilia in the respiratory epithelial tract represent an important innate host defense, SARS-CoV-2 takes advantage of the mucociliary pathway to enhance infection, then facilitate rapid dispersion back into the airways to augment viral shedding, thereby continuing the infection cycle. Omicron variants, which have demonstrated much more rapid spread than earlier SARS-CoV-2 variants, appear to be more efficient at capitalizing on this phenomenon. Epithelial microvilli, motile cilia, and mucociliary-dependent mucus flow encompass another example of how pathogens turn host defenses into vulnerabilities during infection. Understanding these mechanisms may provide clues to develop novel antiviral therapeutics.