TNTs are thin, membranous conduits rich in actin ( 28, 29) that allow the direct transport of cargos including organelles, amyloid proteins ( 28, 30), and viral particles between distant cells ( 30– 35). Here, we investigated the neuroinvasive potential of SARS-CoV-2 and asked whether tunneling nanotubes (TNTs) could be involved in its intercellular spreading. For this reason, it is not clear how the virus can propagate through the brain. While the expression of the ACE2 receptor has been well documented in many cell types and tissues ( 24, 25), in the human brain, ACE2 receptor levels are very low, with the exception of brain areas such as the thalamus and the choroid plexus ( 27). The ACE2 receptor is exposed on the surface of the cells forming the oral cavity and the oropharynx ( 24– 26). Alternatively, in the presence of TMPRSS2 (transmembrane serine protease 2) ( 24) at the plasma membrane (PM), after binding to ACE2 receptor, SARS-CoV-2 uses a fast pH-independent route to enter cells, which allows direct fusion of the virus with the PM ( 23). This is mediated by the proteolytic activation of the S protein that can occur at the endosomes following endocytosis, whereby endosomal acidification triggers endolysosomal proteases priming viral fusion ( 23).
To gain access to the cytosol, SARS-CoV-2 must fuse its envelope with the cell membranes. To enter host cells, the viral spike (S) proteins of CoVs bind the enzymatic domain of the ACE2 receptor. The ACE2 receptor is the main actor responsible for virus entry in the lower respiratory tract ( 13, 21, 22). SARS-CoV-2 neuroinvasion could be achieved through several routes ( 19), and once it reaches the CNS, it could bind the angiotensin-converting enzyme 2 (ACE2) receptor exposed on neuronal cells to infect the brain ( 20). However, how SARS-CoV-2 gains access to the CNS and how infection leads to neurological symptoms are still not clear ( 14– 18). Investigating how SARS-CoV-2 enters neuronal cells is essential for understanding the neurological manifestations associated with COVID-19. In addition, case reports have shown that the brain tissue of patients that died following COVID-19 were positive for SARS-CoV-2 RNA ( 13). The ability of SARS-CoV-2 to enter the central nervous system (CNS) is expected given that several types of CoV have been reported to invade and persist in the CNS (e.g., SARS-CoV and Middle East respiratory syndrome–CoV) ( 11, 12). The neurological symptoms can be acute and resolve with the disease or can represent a major issue in the case of long COVID ( 8– 10). Neurological manifestations of different gravity have also been reported ( 4– 7). Although SARS-CoV-2 primarily targets the respiratory tract and most patients with COVID-19 present severe respiratory symptoms ( 3), other organs such as the intestine, liver, kidneys, heart, and brain can also be affected. Our data highlight a previously unknown mechanism of SARS-CoV-2 spreading, likely used as a route to invade nonpermissive cells and potentiate infection in permissive cells.Ĭoronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been developing into a global pandemic since the first reported events in December 2019 ( 1, 2). Furthermore, multiple vesicular structures such as double-membrane vesicles, sites of viral replication, are observed inside TNTs between permissive and nonpermissive cells.
In cellulo correlative fluorescence and cryo–electron tomography reveal that SARS-CoV-2 is associated with TNTs between permissive cells. SARS-CoV-2 induces the formation of tunneling nanotubes (TNTs) and exploits this route to spread to uninfected cells. We report that human neuronal cells, nonpermissive to infection through the endocytic pathway, can be infected when cocultured with permissive infected epithelial cells. How SARS-CoV-2 gains access to the brain and how infection leads to neurological symptoms are not clear because the principal means of viral entry by endocytosis, the angiotensin-converting enzyme 2 receptor, are barely detectable in the brain. Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represent a major issue in long coronavirus disease.
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