Fig. 4.

Hypothetical TNT-dependent transfer of SARS-CoV-2. Binding of the S protein of SARS-CoV-2 to a heparan sulfate (HS) proteoglycan molecule (which acts as a co-receptor for ACE2 binding) present on the cell surface, induces the formation of a tunneling nanotube (TNT) between the infected cell and a neighboring uninfected cell. The virus is transferred within the lumen of the TNT, which contains actin filaments. Rho GTPase signaling including the Rac1/Cdc42/Pak1 pathways regulates actin polymerization, which is required for the formation of the TNT. The virus can also, after binding to HS, surf on the surface of the TNT. The virus on the surface of the TNT can also be internalized into the TNT interior. Although there are no data showing that SARS-CoV-2 spreads through TNTs, the fact that its S protein binds to HS and that the closely related SARS-CoV-1 can induce various types of cytoplasmic extensions, suggests that it does