Advanced technology (CRISPR) shows that mucus is your body’s first line of defense against viruses

This CRISPR story is part of an extended series on regenerative medicine. For other stories on this topic, see williamhaseltine.com and search for Regenerative Medicine. My definition of regenerative medicine is any medical modality that restores us to normal health when we are damaged by disease, injured by trauma, disadvantaged by birth, or worn down by time. Modalities include: chemicals, genes, proteins and cells used as drugs, gene editing, prosthetics and mind-machine interfaces.

One of the key mysteries of SARS-CoV-2 is why it seems to infect some people more severely than others. Although vaccines have provided much-needed protection against the virus, there is still a need to develop better drugs to treat those who become infected.

A key method for developing drugs that fight viral infection is to determine what the virus needs to replicate in the body. Until now, most studies have focused solely on SARS-CoV-2 and its own methods of attack. But infections require cooperation between the cells of the human body along with the virus. In fact, viruses rely on many cellular structures within host cells to replicate.

So how can we decode SARS-CoV-2 and its interactions with our own bodies? One way to do this is to conduct a systematic study of all genes in cells known to interact with SARS-CoV-2. By inhibiting the majority of genes while leaving some active, scientists can pinpoint exactly which genes and cellular structures are affected by SARS-CoV-2 infections.

Fortunately, with a new gene-editing tool called CRISPR, UC Berkeley researchers have been able to do just that. After conducting a study of genes found in lung cells, Biering et al. discovered a natural protein in the body that may have the ability to inhibit SARS-CoV-2 infections. This study is the first to examine how SARS-CoV-2 interacts with human lung cells, marking a critical advance in SARS-CoV-2 research.

How does CRISPR work? CRISPR technology is a recent advance in gene editing. The technology consists of two components: Cas9, which is an enzyme that cuts DNA, along with a short RNA segment that targets Cas9. When the guide RNA locates its complementary sequence in the DNA, it binds to the target gene and acts as a signal to the Cas9 enzyme. Once Cas9 locates and binds to the guide RNA, the enzyme can cut the entire DNA sequence at that particular location. This allows scientists to knock out genes entirely or edit the genome by inserting new genes.

Biring et al. used CRISPR technology to study genes that exist in human lung epithelial cells. Epithelial cells line the walls of the lungs and are responsible for producing mucus and initiating several immune responses. Lung epithelial cells also express receptors such as ACE2, which are known to influence SARS-CoV-2 infections, making the cells a valuable model for SARS-CoV-2 infections.

After examining the effects of each gene found in lung epithelial cells, Biering et al. found several genes that appear to influence SARS-CoV-2 infections. These include known genes such as those responsible for ACE2 receptors, but also some new players. One of the most influential gene categories was a group responsible for producing proteins called mucins.

Mucins are the most abundant protein in mucus and can either be secreted to form gels that cover the surface of the lungs, or they can exist in the membranes of epithelial cells. Interestingly, Biering et al. found that only mucins in the cell membrane appeared to have a direct effect on the severity of SARS-CoV-2.

To determine whether membrane-bound mucins could have an antiviral effect on SARS-CoV-2 infections, Biering et al. then overexpress mucins. To their surprise, the membrane-bound mucins were able to reduce the severity of SARS-CoV-2 infections. These results are also consistent with the predominant variants of SARS-CoV-2.

These results prompted the researchers to test the relationship between membrane-bound mucins and SARS-CoV-2 in vivo. When Biering et al. compared mice with inactivated mucin genes to those with normally functioning genes, they found that mice with inactivated mucin genes had much higher levels of viral infection contained in their lung tissue.

But how do mucins defend against SARS-CoV-2? Because only membrane-bound mucins affected SARS-CoV-2 infections, Biering et al. suggested that membrane-bound mucins somehow block virus entry into the cell membrane. Surprisingly, after using microscopic imaging techniques to study the interactions between SARS-CoV-2 and mucins, the researchers found that cells with overexpressed mucins indeed inhibited virus entry.

More research needs to be done to determine whether interactions between mucins and SARS-CoV-2 are consistent in humans. However, the results of this study are promising and may lead to new, effective treatments that have the potential to reduce the severity of SARS-CoV-2 infections.

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