SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium re-mains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omi-cron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.

Automated summary

Using primary nasal epithelial organoid cultures, researchers discovered that SARS-CoV-2 attaches to motile cilia through the ACE2 receptor. The virus then traverses the mucus layer using these cilia as tracks to access the cell body. Depletion of cilia inhibits infection not only by SARS-CoV-2 but also other respiratory viruses. Furthermore, the study found that SARS-CoV-2 progeny attach to airway microvilli and trigger the formation of extended and branched microvilli, facilitating viral egress from the microvilli back into the mucus layer. This supports the model of virus dispersion throughout the airway tissue via mucociliary transport. Remarkably, the Omicron variants exhibit higher affinity to motile cilia and demonstrate accelerated viral entry. The findings highlight the critical role of motile cilia, microvilli, and mucociliary-dependent mucus flow in efficient virus replication in nasal epithelia.