ABOVE: A micrograph from the first US case of COVID-19, with SARS-CoV-2 virus particles in blue Hannah A Bullock, Azaibi Tamin

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Viruses typically spread among host cells as virions, particles comprising a cargo of genetic material enveloped by a protein shell. In addition to this so-called cell-free transmission, some viruses can also spread their genetic material by hopping directly from one cell to another via tight junctions, virological synapses, or other mechanisms—a more efficient route that evades host immune defenses.

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Shan-Lu Liu of The Ohio State University and colleagues set out to see if this cell-to-cell transmission occurs in SARS-CoV-2. Engineering pseudotyped virus genomes to include spike protein and fluorescent protein genes, the team tracked viral movement in two cultures: one where cells could touch, and another where cells were physically separated. Neither condition prevented cell-free transmission, but only the first allowed cell-to-cell transmission. 

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The results indicated that around 90 percent of viral transmission was cell-to-cell, possibly via fusion between neighboring infected and uninfected cells, Liu says. Further in vitro experiments that paired authentic SARS-CoV-2 with either the antiviral medication remdesivir or serum samples from people who received mRNA vaccines hinted that cell-to-cell transmission helped the virus avoid being neutralized by drugs or antibodies. This ability to spread without exiting the intracellular environment could help “lead to persistent or prolonged infection,” Liu notes. 

Clare Jolly, a virologist at University College London who was not involved in the work, says Liu’s team presents good experimental evidence for cell-to-cell transmission. It’s less clear how much this happens in vivo or whether it’s a result of cell-cell fusion, she says, noting that other viruses typically use different tactics. “Whether that’s really what the authentic [SARS-CoV-2] virus does in primary epithelial cells is an open question.”

Liu says his lab is now digging into mechanisms and, as the current study focused on the SARS-CoV-2 Alpha and Beta variants, expanding the work to consider Omicron.

C. Zeng et al., “SARS-CoV-2 spreads through cell-to-cell transmission,” PNAS, 119:e2111400119, 2022.