SARS-CoV-2 goes “underground” and spreads cell-to-cell

The virus that causes COVID-19 employs several stealth moves to keep kicking alive, and one of the keys to its success is to spread from the immune system through cell-to-cell transmission. Is to hide.

Cell culture experiments have shown that SARS-CoV-2, which causes COVID-19, limits the release of viral particles that can be inactivated by antibodies and instead is pushed into the cell wall and spreads between cells. I did.

“This is basically an underground form of infection,” said the lead author. Shan Lu Liu, Professor of Virology in the department Veterinary bioscience University researcher at Ohio State University Retrovirus Research Center..

“SARS-CoV-2 can spread efficiently from cell to cell because there is essentially no blocker from the host immunity. The target cell becomes a donor cell and the virus does not come out of the cell. It may just be a wave of spread. “

Liu et al. Discovered other obvious details about SARS-CoV-2. The superficial spike protein alone allows intercellular transmission, but the primary receptor for the virus on the target cell to which the spike binds is not a requirement. Of cell-to-cell transmission operations. In addition, they found that neutralizing antibodies were less effective against the virus if it spread through the cells.

The study will be published today (December 22, 2021) In the journal Minutes of the National Academy of Sciences..

The main point of this study was to compare SARS-CoV-2 with the coronavirus behind the 2003 SARS outbreak known as SARS-CoV. Findings show that the initial outbreak resulted in a much higher case fatality rate, lasting only eight months, but is about to exceed the current two-year pandemic, and the majority of cases are asymptomatic. Helps to explain.

By comparison, SARS-CoV, which caused SARS in 2003, is more than SARS-CoV-2 in so-called cell-free transmission when freely floating virus particles infect target cells by binding to receptors on their surface. Has also been shown to be efficient. It remains vulnerable to antibodies produced by previous infections and vaccines. On the other hand, SARS-CoV-2 is more efficient in cell-to-cell transmission, making it difficult to neutralize with antibodies.

Different efficiencies of the virus were first demonstrated in experiments using pseudoviruses, which are non-infectious viral cores decorated with both types of coronavirus peplomer on the surface.

“Because the only difference between these pseudoviruses was the spike protein, the spike protein is necessary and sufficient for intercellular infections of both SARS-CoV-2 and SARS-CoV,” said Liu, also program director. increase. Viruses and new pathogen programs At the Ohio State University Institute for Infectious Diseases.

Looking deeper into these differences, researchers found that SARS-CoV-2 outperforms SARS-CoV in initiating fusion with the target cell membrane, another important step in the viral entry process. I found that I was there. And its stronger fusion action was associated with enhanced cell-cell transmission of the virus.

Paradoxically, too much cell membrane fusion can lead to cell death and actually prevent cell-to-cell transmission, Liu found.

Next, the team turned to the role of the ACE2 receptor, a cell surface protein that acts as a gateway to the invasion of the virus that causes COVID-19. Researchers have unexpectedly discovered that cells with or without ACE2 levels on the surface can invade the virus and enable strong intercellular transmission.

“There is no complete correlation between SARS-CoV-2 infection and ACE2 levels,” Liu said. “ACE2 may be required for the initial infection, but once the infection is established, the virus can spread from cell to cell and may not require ACE2.”

Finally, in an experiment testing blood samples from human COVID-19 patients against the real SARS-CoV-2 virus, researchers found that the virus could evade antibody responses via cell-cell transmission, but the virus Cell-free transmission mode was effective for antibody neutralization.

“We were able to confirm that cell-to-cell infections were insensitive to antibody inhibition from COVID patients or vaccinated individuals,” Liu said. “The resistance of cell-to-cell transmission to antibody neutralization is probably cautionary as SARS-CoV-2 mutants containing the latest Omicron continue to emerge. In this sense, other stages of viral infection. It is important to develop effective antiviral drugs that target the disease. “

The exact mechanism that the virus uses to spread from cell to cell, how it affects an individual’s response to viral infections, and whether efficient cell-to-cell transmission contributes to the emergence and spread of new things. There are still many unknown variants, such as. Liu’s lab is planning additional studies using real viruses and human lung cells to further investigate these questions.

This work was supported by a grant from the National Institutes of Health and funding from an anonymous private donor to Ohio.

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