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

The study titled “SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming” offers crucial insights into how SARS-CoV-2 infects nasal epithelium.

Here’s a detailed summary:

  1. Key Findings:
    • SARS-CoV-2 attaches to motile cilia in nasal epithelium using the ACE2 receptor, using these cilia as tracks to access cell bodies. Blocking cilia formation inhibits infection, suggesting their critical role in viral entry.
    • The virus induces the formation of elongated and highly branched microvilli on airway cells, which are key for viral egress and spreading. This microvillar remodeling is regulated by p21-activated kinases (PAK).
    • Omicron variants show an accelerated rate of infection and a higher affinity for binding to motile cilia compared to previous strains​​.
  2. Viral Entry and Spread Mechanism:
    • The study details a two-step infection process. Initially, a few ciliated human nasal epithelial cells (HNEs) are infected, followed by rapid spread to neighboring cells.
    • The virus attaches to cilia during the early stages of infection. Treatments that disrupt the mucin layer increase virus entry, indicating that the mucin layer ordinarily blocks infection.
    • The study proposes two models for SARS-CoV-2 entry: one involving ciliary membrane fusion and another involving transport of the virus from the cilia tip to the cell body​​.
  3. Role of Microvilli in Infection:
    • Microvilli play a significant role in the later stages of infection. Infected cells show a dramatic increase in the length and branching of microvilli, which then accumulate viral particles.
    • Inhibiting microvillar core proteins reduces infection, underscoring the importance of microvilli in viral egress rather than entry​​.
  4. Mucociliary Transport and Virus Spread:
    • The study suggests that SARS-CoV-2 uses mucociliary transport to spread within the airway tract. In patients with primary ciliary dyskinesia (PCD), who have reduced mucociliary transport, the spread of the virus was limited compared to normal cases​​.
  5. Regulation by PAK Kinases:
    • PAK kinases are identified as crucial regulators of microvillar dynamics during SARS-CoV-2 infection. Inhibiting these kinases reduces the number of SARS-CoV-2-positive cells, indicating their role in viral replication and spreading​​.
  6. Omicron Variant Efficiency:
    • Omicron variants are found to be more efficient in infecting nasal epithelium cultures, with an increased rate of early infections. This might be due to stronger binding of Omicron to motile cilia​​.

In summary, this study provides comprehensive insights into the mechanisms of SARS-CoV-2 infection, emphasizing the roles of motile cilia, microvilli, mucociliary transport, and kinase regulation in viral entry, replication, and spreading, with significant implications for understanding and targeting the virus.

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