SARS-CoV-2 goes 'underground' to spread from cell to cell
Study sheds light on COVID virus transmissibility, resistance to host
immunity

Date:
December 23, 2021
Source:
Ohio State University
Summary:
The virus that causes COVID-19 has adopted some stealth moves to
stay alive and kicking, and one secret to its success is hiding from
the immune system by spreading through cell-to-cell transmission,
a new study has found.



FULL STORY ==========================================================================
The virus that causes COVID-19 has adopted some stealth moves to stay
alive and kicking, and one secret to its success is hiding from the
immune system by spreading through cell-to-cell transmission, a new
study has found.


==========================================================================
Cell culture experiments showed that SARS-CoV-2, 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.

"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 and colleagues found other revealing
details about SARS-CoV-2: 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. Additionally, they found that neutralizing antibodies are less effective against the virus when it
spreads through cells.

The research was published Wednesday (Dec. 22, 2021) in the journal
Proceedings of the National Academy of Sciences.



==========================================================================
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 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, Liu said.

The 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.

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
can 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 acts as the gateway for entry of the virus that
causes 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 infection is established, the virus may not need ACE2 anymore
because it can spread from cell to cell." 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." 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. 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.

========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Emily Caldwell. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Cong Zeng, John P. Evans, Tiffany King, Yi-Min Zheng, Eugene
M. Oltz,
Sean P. J. Whelan, Linda J. Saif, Mark E. Peeples,
Shan-Lu Liu. SARS-CoV- 2 spreads through cell-to-cell
transmission. Proceedings of the National Academy of Sciences,
2021; 119 (1): e2111400119 DOI: 10.1073/ pnas.2111400119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211223113127.htm

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