Human lung protein can promote or prevent SARS-CoV-2 infection

Researchers take important step toward understanding the microscopic battle waged between our lung cells and the SARS-CoV-2 virus that causes COVID-19 step. A UC Berkeley-led study has identified specific proteins in our body that either promote or protect us from SARS-CoV-2 infection, potentially opening the door to new antiviral treatments.

In this study, published this week in Nature Genetics , the researchers used CRISPR technology to test the effect of each human gene on SARS-CoV-2 infection in human lung cells. Their findings reveal new pathways that viruses rely on to infect cells, as well as antiviral pathways that help prevent viral infection. Notably, they found that mucin — the main component of mucus found in the lungs — appears to help prevent the SARS-CoV-2 virus from entering our cells.

“Our data suggest that mucins play a key role in limiting SARS-CoV-2 infection, which can act as a The barrier for viruses that try to get into our lung epithelial cells,” said the study’s Scott Biering, co-lead author and postdoctoral researcher in the lab of Eva Harris at the UC Berkeley School of Public Health. “Furthermore, our data suggest that the level of mucin expression in an individual’s lung may influence the progression of COVID-19 disease.”

Patrick Hsu – co-founder of the Arc Institute and Berkeley Assistant Professor of Bioengineering, a Deb Institute Fellow and a Research Fellow at the Institute for Innovative Genomics – is the principal investigator of the study, which brought together researchers from 10 institutions. Harris, professor of public health at UC Berkeley, and Silvana Konaman, assistant professor at Stanford University School of Medicine, are co-senior authors of the study. Other collaborators come from Stanford University, UNC-Chapel Hill, Yale University School of Medicine and Cornell University and cover disciplines such as immunology, bioengineering, epidemiology, molecular biology and genetics.

Together, researchers are trying to determine how the SARS-CoV-2 virus enters human cells and replicates so efficiently during illness. They also want to identify specific defense mechanisms in human cells that may be able to fight infection, which could inspire new therapeutic strategies.

Researchers have found that the types of mucins MUC1 and MUC4 found in the membranes of lung cells protect lung cells from infection. The finding is important because previous research has suggested that a buildup of mucus may be the cause of some people becoming seriously ill with COVID-19 — because mucus can make it difficult for people to breathe — and suggested drugs to deplete it. The Berkeley-led study suggests that this strategy may interfere with mucins, which provide a valuable defense mechanism against SARS-CoV-2 infection.

Still, mucins are complex and more research is needed to fully understand them. The researchers found that other mucins secreted into the mucus lining of the lungs, MUC5AC and MUC5B, either did not help prevent SARS-CoV-2 infection, or even facilitated viral infection.

According to Biering, the type and amount of mucus produced by each individual may lead to different outcomes of SARS-CoV-2 infection – and lead to different treatment strategies.

“People who produce lots of the right type of mucus are probably well protected. But people who produce lots of mucus are the wrong type There may be a greater risk of infection with mucus,” Biering said. “And those who produce very few of the correct types may also be at greater risk.”

This is also the first study In it, the researchers studied how the SARS-CoV-2 virus interacts with human lung cells, marking a major advance in COVID-19 research.

“Our own proteins are known to promote or inhibit viral infection,” Biering said. “But this is the first systematic study of these host cell proteins in human lung epithelial cells in response to SARS-CoV-2 infection.”

Past studies of SARS-CoV-2 infection have used cell types that do not naturally contain the receptors or other pathways that the virus uses to infect our lungs. For this study, the researchers wanted to use a more related cell type, human epithelial cells, called Calu-3, which are found on the inner surface of the lung. Although working with this cell line is extremely challenging, the researchers managed to gain a more precise understanding of the biology involved in human SARS-CoV-2 infection.

“[The use of Calu-3 cells] is a huge improvement, as these cells are very representative of the way the virus contacts and infects humans ​​The first cells, and it revealed new pathways not seen in other cell lines,” said co-lead author Sylvia Sarnik, an assistant specialist in the research Shi Xu lab. “Overall, this study is a step forward in understanding how the virus is infected and paves the way for future research into better treatments.”

Researchers performed genome-wide CRISPR gain-of-function and loss-of-function screens to eliminate or overexpress every gene in the human genome. They then measured the effect of these gene expression changes on SARS-CoV-2 infection in human lung epithelial cells. Importantly, many of the genes highlighted by this screen have not yet been studied experimentally, providing a starting point for future work.

“You can run these massively parallel ‘Hunger Games’-style experiments on human cells and see what you can change Which genes adjust the ability of our lung cells to survive or grow when viruses infect them,” Hsu said.

“Our screen successfully identified hundreds of genes important for SARS-CoV-2 replication and hundreds of Gene-2 ​​that may limit SARS-CoV,” Billing said. “In this study, we chose to focus on understanding the role of these mucins.”

The researchers put the mucin sugars The protein was identified as a key limiting factor for cellular infection, both in mouse models and in humans.

The researchers also studied how mucin interacts with other respiratory viruses, including influenza A, human parainfluenza, common Cold coronavirus and respiratory syncytial virus. As with SARS-CoV-2, the results are unpredictable.

“We found that mucins have broad antiviral effects, but the story is actually a lot more complicated than that,” Xu said . “In fact, in some viruses, we found that mucin overexpression actually seems to increase infectivity.”

Future work will be crucial to better understand how viruses interact with mucins, but for now, these findings provide an important starting point. “This study helps us learn more about the virus and opens up new avenues for further research into druggable targets,” Sarnik said.

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