Early human embryonic cells may be vulnerable to SARS-CoV-2 infection

A University of California, Riverside study reports that cells in the earliest stages of human development could be susceptible to infection by SARS-CoV-2, which causes COVID-19, offering new insight into how the virus interacts with developing human tissues and why that may matter for pregnancy research.

Using a "disease-in-a-dish" laboratory model of early human embryonic development, researchers Ann Song and Prue Talbot examined how different cell types respond to exposure to artificial SARS-CoV-2-like particles. They found that multiple early embryonic cell types can be infected, but susceptibility varies significantly. Cells destined to become the ectoderm - the layer that eventually forms the skin and nervous system - were by far the most vulnerable.

"Ectodermal cells were about 23 times more susceptible to infection than undifferentiated embryonic stem cells and six times more susceptible than mesodermal cells," said Song, a doctoral student in the Department of Molecular, Cell and Systems Biology and the first author of the study published in Frontiers in Cell and Developmental Biology. Mesodermal cells are the middle layer of embryonic stem cells that differentiate into essential tissues.

The heightened vulnerability appears to be driven by several biological features. The researchers found ectoderm cells show elevated activity of TMPRSS2, a protein that helps the virus enter cells. In addition, these cells have a thinner glycocalyx, a protective sugar coating, making it easier for the virus to bind to the ACE2 receptor - a membrane-bound protein that acts as the primary entry point for the SARS-CoV-2 virus - on the cell surface.

"Together, these factors create conditions that strongly favor viral attachment and entry and highlight how certain early cell types may be particularly permissive to infection," said Talbot, a professor of the graduate division and Song's advisor.

Song said the findings highlight an urgent need for clinical studies to monitor the long-term neurological and developmental health of infants born to mothers who were infected with COVID-19 during early pregnancy.

"Our findings highlight urgent need for clinical studies to monitor the long-term neurological and developmental health of infants born to mothers who were infected with COVID-19 during early pregnancy," she said.

The study was conducted using experimental models rather than in pregnant individuals. The findings do not demonstrate that embryos are infected during real pregnancies, but they do show that, in principle, very early developmental stages could be biologically susceptible to the virus.

The results provide insight into the first weeks of human development (weeks 1-4), a period that is difficult to study directly. Because the ectoderm gives rise to the brain and nervous system, its high susceptibility raises important questions about potential developmental risks. If infection were to occur during this stage, it could contribute to neurodevelopmental delays or structural abnormalities.

"This study gives us a clearer picture of how SARS-CoV-2 can interact with human cells at the earliest stages of life," Talbot said. "Further research will be needed to understand the real-world implications."

The research was supported in part by the Tobacco-Related Disease Research Program and various research awards and fellowships.

The title of the paper is "SARS-CoV-2 pseudoparticles preferentially infect ectoderm in human embryonic tissues."