Why some people become sicker with covid-19 than others has been one of the most puzzling aspects of this virus from the beginning.
“Why some people get more sick than others has been one of the most puzzling aspects of this virus from the beginning,” says the study author.
“Many studies looking for risk predictors have looked for signatures in the blood, but blood may not really be the right place to look.”
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In the first stages of infection, the body’s first contact with SARS-CoV-2, the virus underlying COVID-19, occurs in the nose and throat, often referred to as the nasopharynx.
The Cell research indicates that the early reactions in this battlefield play a crucial role in determining who will have more severe sickness and who will be spared entirely.
The researchers sequenced each cell’s RNA in order to get a more precise picture of what goes on in the nasopharynx.
For a sense of all the work this entailed, each patient swab yielded an average of 562 cells.
By studying the RNA data, the researchers were able to The RNA data enabled the team to pinpoint which cells were present, which contained RNA originating from the virus — an indication of infection — and which genes the cells were turning on and off in response.
It soon became clear that the epithelial cells lining the nose and throat undergo major changes in the presence of SARS-CoV-2. The cells diversified in type overall.
There was an increase in mucus-producing secretory and goblet cells. At the same time, there was a striking loss of mature ciliated cells, which sweep the airways, together with an increase in immature ciliated cells (which were perhaps trying to compensate).
The team found SARS-CoV-2 RNA in a diverse range of cell types, including immature ciliated cells and specific subtypes of secretory cells, goblet cells, and squamous cells.
The infected cells, as compared to the uninfected “bystander” cells, had more genes turned on that are involved in a productive response to infection.
The key finding came when the team compared nasopharyngeal swabs from people with different severity of COVID-19 illness:
- In people with mild or moderate COVID-19, epithelial cells showed increased activation of genes involved with antiviral responses — especially genes stimulated by type I interferon, a very early alarm that rallies the broader immune system.
- In people who developed severe COVID-19, requiring mechanical ventilation, antiviral responses were markedly blunted. In particular, their epithelial cells had a muted response to interferon, despite harboring high amounts of virus. At the same time, their swabs had increased numbers of macrophages and other immune cells that boost inflammatory responses.
“Everyone with severe COVID-19 had a blunted interferon response early on in their epithelial cells, and were never able to ramp up a defense,” said the study autors.
“Having the right amount of interferon at the right time could be at the crux of dealing with SARS-CoV-2 and other viruses.”
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