In a new study published on the preprint server bioRxiv* scientists are investigating the neuroinvasive potential of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the role of tunneling nanotubes (TNTs) in spreading the virus to adjacent cells. The findings from this study reveal that neuronal cells are not permissive to SARS-CoV-2 through an exocytosis/endocytosis dependent pathway; however, they can be infected when co-cultured with permissive infected epithelial cells.
Researchers discovered that SARS CoV-2 causes TNT between cells. They then use this route to invade non-infected cells in coculture.
Study: Tunneling nanotubes provide a novel method for spreading SARS-CoV-2 between permissive cells as well as to neurons that are not permissive. Image Credit: Alexander Limbach / Shutterstock.com
Differential neurological manifestations that are associated with the coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, have been reported. Although acute neurological symptoms can disappear over time, they are often persisting throughout long-term COVID. It is not clear how SARS-CoV-2 interacts with the central nervous system (CNS) at present.
SARS-CoV-2 binds its spike protein to the host cell’s surface angiotensin-converting receptor 2 (ACE2) to gain entry. ACE2 receptors can be found in the liver, lungs kidneys, heart, organs, kidneys, intestines and kidneys. It is only found in certain regions like the thalamus and choroid plexus, that it is found in the human brain. Despite the absence of ACE2 receptors in brain, SARS/CoV-2 has been shown to spread throughout the brain ain the brain tissues of COVID-19 decedents.
In a prior study, scientists have shown a novel mechanism of cell-to-cell communication by spreading amyloid aggregates from the CNS and from the lymphoid system’s peripheral lymphoid cells to neurons via TNTs.
TNTs are dynamic connections between cells that consist of membranous channels that are thin and rich in actin that form continuous cytoplasmic bridges between cells that span short and long distances. These TNTs can be used for transporting cargo, including viruses between cells.
Numerous recent studies have revealed the development of TNTs or TNT-like structures that were triggered by retroviruses, herpesviruses, influenza A and the human metapneumovirus to facilitate the effective spread of infection to neighboring healthy cells. The current study was inspired by these observations and examined the role of TNTs in the neuroinvasive potential SARS-CoV-2.
In addition, the researchers discovered that when viruses are transferred through TNTs the virus is able to do not have neutralizing antibodies and immune surveillance. They can also infiltrate cells that are less tolerant like cells that lack the receptor for virus entry. Thus, the viruses favorably trigger TNT production to allow for the spread of virus tropism as well as pathogenicity.
Researchers investigated the susceptibility of different cell types to the virus by the receptor-mediated pathway to understand the way in which SARS-CoV-2 impacts neuronal cells. This study employed human colon epithelial cells (Caco-2) as well as monkey kidney epithelial cells-line (Vero E6) and human (SH-SY5YY) and murine neuronal cell lines (CAD).
Scientists discovered that SARS-CoV-2 was more susceptible to infection in epithelial Vero E6 cells and Caco-2 cells than in neuronal cells. However, when they co-culturing them, they found that the virus spread via a cell-to-cell contact-dependent mechanism and that it was actively replicating in the neuronal cells. Thus, the scientists established that the SARS-CoV-2 can spread among cells through an exocytosis/endocytosis independent pathway.
Probing the direct cell-to-cell contact-dependent manner of the viral spread in neuronal cells, scientists examined whether the virus triggers the formation of TNTs or TNT-like structures within the infected cells and makes use of these structures to spread to cells that are not infected. Using confocal microscopy, the scientists confirmed that TNTs contribute to the SARS-CoV-2 transmission.
Scientists have developed an interrelative fluorescent and cryoelectron microscope approach as well as a tomography technique to determine the nature and the structure of the viral particles shared with TNTs and their transfer mechanism.
Incredibly, the images showed viral compartments in TNTs. This was evident in the form membranous structures in different sizes that resemble double-membrane vesicles in the tube between permissive (Vero E6 infected cells) and non-permissive cells (SH-SY5Y mCherry cells).
Further, they also confirmed that these TNTs facilitate SARS-CoV-2 transmission between the permissive Vero E6 cells through a secretion-independent pathway. Between these cells they observed that the SARS-CoV-2 particles decorating the TNTs on their surface displayed both an ellipsoidal- and spherical-enveloped morphology , with an average diameter ranging from 50 to 100 nanometers (nm), typically of coronavirus. Here, the cryo-EM images revealed SARS-Cov-2 on top the TNTs, which was different from the observations in neuronal cells.
This study provides new details about the structure of the viral particles involved in intercellular spread and important information on the mechanism that allows SARS-CoV-2 to transmit in neuronal cells.
Further, this study shows the remarkable role of the TNTs that are induced in the transmission of the virus in permissive as well as non-permissive cells. This could help increase the efficiency of the viral spread throughout the body. This study is the first to establish that TNTs could be a possible way to spread SARS-CoV-2 according to the scientists.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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