Study: SARS-CoV-2 hides spreading from cell to cell

A new study has found that SARS-CoV-2 has been hiding from the immune system by spreading from cell to cell.

The research has been published in the 'Proceedings of the National Academy of Sciences Journal'.

"It's basically an underground form of transmission," said lead author 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.

"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," Liu added.

Liu and colleagues found other revealing details about SARS-CoV-2: The spike protein on its surface alone enabled cell-to-cell transmission, and yet the virus's primary receptor on target cells -- to which the spike bound -- is not a necessary part of the cell-to-cell transmission operation. Additionally, they found that neutralizing antibodies are less effective against the virus when it spreads through cells.

A major point of this study was comparing SARS-CoV-2 to the coronavirus behind the 2003 SARS outbreak, known as SARS-CoV. The findings helped 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, Liu said.

The comparison showed that the SARS-CoV that caused SARS in 2003 was more efficient than SARS-CoV-2 at what is called cell-free transmission when freely floating viral particles infected target cells by binding to a receptor on their surface -- but also remained 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.

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.

"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," said Liu, also a program director of the Viruses and Emerging Pathogens Program in Ohio State's Infectious Diseases Institute.

Looking more deeply into those differences, the researchers 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.

Paradoxically, too much cell membrane fusion leads to cell death and could actually interfere with cell-to-cell transmission, Liu also found.

The team then turned to the role of the ACE2 receptor, a protein on cell surfaces that acted as the gateway for the entry of the virus that caused COVID-19. The researchers 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.

"There is no perfect correlation between SARS-CoV-2 infection and the level of ACE2," Liu said.

"ACE2 may be needed for initial infection, but once the infection is established, the virus may not need ACE2 anymore because it can spread from cell to cell," Liu added.

Finally, in experiments testing blood samples from human COVID-19 patients against the authentic SARS-CoV-2 virus, researchers 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.

"We were able to confirm cell-to-cell transmission is not sensitive to inhibition from antibodies from COVID patients or vaccinated individuals," Liu said.

"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," Liu explained.

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 contributed to the emergence and spread of new variants. Liu's lab is planning additional studies using the authentic virus and human lung cells to further explore these questions.

This work was supported by grants from the National Institutes of Health and funds from an anonymous private donor to Ohio State.

Ohio State co-authors include Cong Zeng, Jack Evans, Tiffany King, Yi-Min Zheng, Eugene Oltz, Linda Saif and Mark Peeples, also a researcher at Nationwide Children's Hospital. Sean Whelan of the Washington University School of Medicine also contributed.