Ohio State University Study Shows That SARS-CoV-2 Is Adopting A ‘Covert’ Strategy Of Spreading From Cell To Cell In The Human Host
Researchers from Ohio State University have found that the novel coronavirus and its variants are adopting some stealth and covert moves to stay alive and kicking, and one secret to its success and survival is hiding from the human host’s immune system by spreading through cell-to-cell transmission.
The study team provided evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity.
Importantly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism.
Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients.
Although angiotensin-converting enzyme 2 enhances cell-to-cell transmission, the study findings found that it is not absolutely required. (This has vast implications as it shows that the novel coronavirus can reach deep tissues and organs of the human host that do not have ACE2 receptors!)
Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission.
The study findings revealed critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.
The study findings were published in the peer reviewed journal: Proceedings of the National Academy of Sciences. https://www.pnas.org/content/119/1/e2111400119
New cell culture experiments showed that the SARS-CoV-2 coronavirus, which causes COVID-19, limits the release of viral particles that can be inactivated by antibodies, instead staying tucked within cell walls and spreading between cells.
Lead author Dr Shan-Lu Liu, a virology professor in the Department of Veterinary Biosciences at The Ohio State University and an investigator in the university’s Center for Retrovirus Research told Thailand Medical News
, “It’s basically an underground form of transmission. SARS-CoV-2 can spread efficiently from cell to cell because there are essentially no blockers from the host immunity. Target cells become donor cells, and it just becomes a wave of spread, as the virus may not get out of the cells.”
The study team found other revealing details about SARS-CoV-2 ie. the spike protein on its surface alone enables cell-to-cell transmission, and yet the virus’s primary receptor on target cells to which the spike binds is not a necessary part of the cell-to-cell transmission operation.
Alarmingly, another significant detail
they found was that neutralizing antibodies are less effective against the virus when it spreads through cells.
A key and critical point of this research was comparing SARS-CoV-2 to the coronavirus behind the 2003 SARS outbreak, known as SARS-CoV.
Dr Liu added, “The study findings help explain why while the first outbreak led to much higher fatality rates and lasted only eight months, we’re about to surpass the two-year mark of the current pandemic, with a majority of cases being asymptomatic.”
The detailed comparison showed that the SARS-CoV that caused SARS in 2003 is more efficient than SARS-CoV-2 at what is called cell-free transmission, when freely floating viral particles infect target cells by binding to a receptor on their surface but also remain vulnerable to antibodies produced by previous infection and vaccines.
SARS-CoV-2, on the other hand, is more efficient at cell-to-cell transmission which makes it harder to neutralize with antibodies.
Both the viruses’ differing efficiencies were first demonstrated in experiments using pseudoviruses - a non-infectious viral core decorated with both kinds of coronavirus spike proteins on the surface.
Dr Liu who is also a program director of the Viruses and Emerging Pathogens Program in Ohio State’s Infectious Diseases Institute further added, “The spike protein is necessary and sufficient for both SARS-CoV-2 and SARS-CoV cell-to-cell transmission because the only difference in these pseudoviruses were the spike proteins.”
Studying more deeply into those differences, the research team found that SARS-CoV-2 is also more capable than SARS-CoV at initiating fusion with a target cell membrane, another key step in the viral entry process. And that stronger fusion action was associated with the virus’s enhanced cell-to-cell transmission.
However, paradoxically, too much cell membrane fusion leads to cell death and can actually interfere with cell-to-cell transmission, Dr Liu also found.
The study team then turned to the role of the ACE2 receptor, a protein on cell surfaces that acts as the gateway for entry of the virus that causes COVID-19.
The team found, unexpectedly, that cells with no or low levels of ACE2 on their surfaces can be penetrated by the virus, enabling robust cell-to-cell transmission.
Dr Liu stressed, “There is no perfect correlation between SARS-CoV-2 infection and the level of ACE2. ACE2 may be needed for initial infection, but once infection is established, the novel coronavirus may not need ACE2 anymore because it can spread from cell to cell.”
Lastly, in experiments testing blood samples from human COVID-19 patients against the authentic SARS-CoV-2 virus, the stud team determined that the virus could evade an antibody response through cell-to-cell transmission, but that antibody neutralization of the virus in the cell-free transmission mode was effective.
Dr Liu said, “We were able to confirm cell-to-cell transmission is not sensitive to inhibition from antibodies from COVID patients or vaccinated individuals. Cell-to-cell transmission’s resistance to antibody neutralization is probably something we should watch for as SARS-CoV-2 variants continue to emerge, including the most recent, Omicron. In this sense, developing effective antiviral drugs targeting other steps of viral infection is critical.”
However, there are still many unknowns, including the exact mechanism the virus uses to spread from cell to cell, how that may influence individuals’ responses to viral infection, and whether or not efficient cell-to-cell transmission contributes to the emergence and spread of new variants.
Dr Liu’s lab is planning additional studies using the authentic virus and human lung cells to further explore these questions.
The study was supported by grants from the National Institutes of Health and funds from an anonymous private donor to Ohio State.
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