A CRISPR screen has shown that certain mucins are protective against SARS-CoV-2, and that expression levels of these proteins can impact disease progression.
“It is well known that virus infection can be promoted or inhibited by our own proteins,” said Scott Biering, the study’s co-lead author and a postdoctoral researcher in Eva Harris’s lab at UC Berkeley’s School of Public Health. “But this is the first time that a systematic investigation of these host cell proteins has been conducted in human lung epithelial cells for SARS-CoV-2 infection.”
In the study, published this week in Nature Genetics, researchers used CRISPR technology to test the impact of every human gene on SARS-CoV-2 infections in human lung cells. Their findings revealed new pathways that the virus relies on to infect cells, as well as the antiviral pathways that help protect against viral infection. Notably, they showed that some mucins, the main component of mucus, seem to help block the SARS-CoV-2 virus from entering cells.
Patrick Hsu, cofounder of the Arc Institute and Berkeley assistant professor of bioengineering, Deb Faculty Fellow and Innovative Genomics Institute Investigator, is the principal investigator of the study, which brought together researchers from ten institutions.
The team discovered that MUC1 and MUC4 defend lung cells from infection. This finding is especially important because previous studies suggested that an accumulation of mucus could be the reason why some people became seriously ill with COVID-19 and using drugs to deplete mucus might be beneficial. This study suggests that such a strategy could interfere with mucins that provide a valuable defense mechanism against SARS-CoV-2 infection.
But other mucins — MUC5AC and MUC5B — either do nothing to stop SARS-CoV-2 infection or can even promote viral infection.
According to Biering, both the type and amount of mucus that each person produces may result in different outcomes for SARS-CoV-2 infection and suggest different treatment strategies.
“Somebody who produces a lot of the right type of mucus could be very protected. But somebody who produces a lot of the wrong type of mucus might have more risk of infection,” said Biering. “And somebody who produces very little of the right type also could be at more risk.”
Since the start of the pandemic, CRISPR screens have been used to find genes related to the disease, including in the lungs.
But past studies of SARS-CoV-2 infection, these researchers say, have used cell types that do not naturally contain the receptors or other pathways that the virus uses to infect our lungs. These researchers wanted to use a more relevant cell type, human epithelial cells called Calu-3, found on the inner surface of the lung. Though this cell line is extremely challenging to work with, researchers managed to gain a more accurate understanding of the biology involved in human SARS-CoV-2 infections.
“[Using Calu-3 cells] was a huge advancement, given that these are very representative of the first cells the virus contacts and infects in humans, and it revealed new pathways not seen in other cell lines,” said co-lead author Sylvia Sarnik, an assistant specialist in Hsu’s lab at the time of the study. “Overall, this study is a step forward in understanding viral infection pathways and paves the way for research toward better treatments in the future.”
“You can run these massively parallel ‘Hunger Games’-style experiments on human cells to see which genes you can change to tune the ability of our lung cells to survive or grow when the virus infects them,” said Hsu.
“Our screen successfully identified hundreds of genes that were important for replication of SARS-CoV-2 and hundreds of genes that could restrict SARS-CoV-2,” said Biering. “In this study, we chose to focus on understanding the role of these mucin proteins.”