An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy

Abstract

SARS-CoV-2 virions enter the host cells by docking their spike glycoproteins to the membrane-bound Angiotensin Converting Enzyme 2. After intracellular assembly, the newly formed virions are released from the infected cells to propagate the infection, using the extra-cytoplasmic ACE2 docking mechanism. However, the molecular events underpinning SARS-CoV-2 transmission between host cells are not fully understood. Here, we report the findings of a scanning Helium-ion microscopy study performed on Vero E6 cells infected with mNeonGreen-expressing SARS-CoV-2. Our data reveal, with unprecedented resolution, the presence of: 1)-long tunneling nanotubes that connect two or more host cells over submillimeter distances; 2)-large scale multiple cell fusion events (syncytia); and 3)-abundant extracellular vesicles of various sizes. Taken together, these ultrastructural features describe a novel intra-cytoplasmic connection among SARS-CoV-2 infected cells that may act as an alternative route of viral transmission, disengaged from the well-known extra-cytoplasmic ACE2 docking mechanism. Our findings may explain the elusiveness of SARS-CoV-2 to survive from the immune surveillance of the infected host.

SARS-CoV-2 Intermittent Virulence as A Result of Natural Selection

“…This is significant because using a variety of receptors allows for switching between different cell types and, thus, different entry gateways [71]. Notably, SARS-CoV-2 can infect non-permissive cells (which do not harbor ACE2 receptors) by using an innovative intra-cytoplasmic connection mechanism that could serve as an alternative viral transmission pathway, independent of the canonical extra-cytoplasmic ACE2 binding mechanism [79].…”