Study sheds light on COVID virus transmissibility, resistance to host
immunity.
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 recently 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.
Reference:
SARS-CoV-2 spreads through cell-to-cell transmission” by Cong Zeng, John P.
Evans, Tiffany King, Yi-Min Zheng, Eugene M. Oltz, Sean P. J. Whelan, Linda
J. Saif, Mark E. Peeples and Shan-Lu Liu, 22 December 2021, Proceedings of
the National Academy of Sciences.
DOI: 10.1073/pnas.2111400119