Cell-to-cell contact helps in spreading SARS-CoV-2, finds study

People aren’t the only ones who should be social distancing — new research shows our cells need to as well. Researchers from Ohio State University in Columbus, Ohio, USA, used in-culture techniques to confirm severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission via cell-to-cell contact.

While the angiotensin-converting enzyme 2 (ACE2) receptor is the entry point for viral infection of a host cell, results show its presence is not required for spreading the virus.

Study: SARS-CoV-2 Spreads through Cell-to-Cell Transmission. Image Credit: Juan Gaertner / Shutterstock

Previous work has shown evidence of cell-to-cell contact in other viruses, including HIV, HCV, EBOV, and other plant viruses. However, the mode of transmission for coronaviruses remained relatively unknown for cell-free infection. The results will help better understand how SARS-CoV-2 rapidly spreads in the body — including the pathogenicity of SARS-CoV-2 variants of concern B.1.1.7 and B.1.351.

Results from this in vitro study reveal the heretofore unrecognized role of cell-to-cell transmission that potentially impacts SARS-CoV-2 spread, pathogenesis and shielding from antibodies in vivo,” wrote the team.

The study “SARS-CoV-2 Spreads through Cell-to-Cell Transmission” is available as a preprint on the bioRxiv* server.

Evidence of cell-free infection for SARS-CoV-2 and greater efficiency in infecting cells

The study authors used cell cultures to investigate potential cell-to-cell SARS-CoV-2 transmission in the context of cell-free infection. Lentiviral pseudotypes and replication-competent recombinant VSV were used to express either the SARS-CoV-2 or SARS-CoV spike protein.

To our knowledge, this is the first direct comparison of cell-to-cell transmission vs. cell-free infection between SARS-CoV-2 and SARS410 CoV in cultured cells, and the results provide important insights into two distinct modes of infection and the host-viral factors that regulate these processes.”

The virus expressing the SARS-CoV-2 spike protein had greater cell-cell fusion activity than the SARS-CoV spike protein, suggesting it is more effective in mediating cell-to-cell transmission.

The SARS-CoV-2 spike protein also showed evidence of fine control of the spike-induced cell-cell fusion — reducing the risk of giant syncytia formation and cell death. Furthermore, when the researchers applied the membrane fusion inhibitor EK1, it weakened cell-to-cell transmission, suggesting SARS-CoV-2 operates through cell-cell fusion.

The presence of ACE2 also enhanced cell-to-cell transmission for both SARS-CoV-2 and SARS-CoV. However, further cellular work using H520 cells and human peripheral blood mononuclear cells with minimal ACE2 presence showed fusion activity, indicating that ACE2 is not necessary for cell-to-cell transmission.

There was also no evidence of cell-free infection.

To look at other factors that affect the transmission, the researchers introduced the CatL inhibitor III to block the endosomal entry pathway by blocking cleave of the viral glycoprotein and neutralizing the endosomal pH.

Results showed that cell-to-cell contact decreased, suggesting transmission is also modulated by endosomal entry and pathways. The inhibitors were less potent for lowering cell-to-cell transmission than cell-free infection, and they showed a weaker inhibitory effect towards SARS-CoV-2 than SARS-CoV.

These observations collectively suggest a less dominant role for the endosomal entry pathway in cell-to-cell transmission of SARS-CoV-2.”

Cell-to-cell transmission may explain immune evasion

New SARS-CoV-2 variants have emerged with the ability to evade vaccine-induced antibodies. The researchers evaluated the role of SARS-CoV-2 cell-to-cell transmission and how it influences immune evasion. In addition, they added neutralizing monoclonal antibodies and convalescent plasma from recovered individuals previously infected with COVID-19.

The antibody treatments almost completely neutralized cell-free infection of SARS-CoV-2. However, when viruses expressed the spike protein of either the B.1.351, B.1.1.7, or the D614G variant, there were increases in cell-free infectivity but comparable cell-to-cell contact.

The B.1351 variant was more resistant to convalescent sera in cell-free infection. In contrast, the B.1.1.7 variant was more resistant to cell-to-cell transmission.

“The cell-free route is directly linked to the ability of viruses to infect target cells and result in spreading among humans through person-to-person contact. In contrast, cell-to-cell transmission has dominant roles in viral pathogenesis and disease progression,” concluded the research team.

Study limitations

The study results suggest greater viral infectivity from SARS-CoV-2 than the SARS-CoV virus. However, the findings require additional research comparing both viruses in the primary human lung and airway epithelial cells.

ACE2 plays an important role in the viral entry of host cells, but the researchers note that other host cofactors such as TMPRSS2 can also influence infectivity. Thus, future work would need to expand on other factors modulating SARS-CoV-2 disease progression and pathogenesis.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.