Viruses infect people every day. From the common cold to influenza, COVID, and more, viruses are part of life. Most of the time, some extra rest, facial tissues, and over-the-counter drugs get us back on our feet, but sometimes, as in the COVID-19 pandemic, viruses not only disrupt an individual’s life, but they can also cause high mortality rates and global shutdowns.
Historically, researchers have looked at individual viruses to figure out best treatment paths, but with hundreds of viruses able to cause disease in humans and hundreds of thousands more that can infect mammals, making treatments for each virus is costly and time prohibitive.
Nicholas Heaton, PhD, professor of molecular genetics and microbiology, is instead looking at host-targeted treatments. “If you target a viral protein directly, you give the virus an opportunity to accumulate mutations,” Heaton said. “But theoretically, if the virus has evolved to use something in the host, and you change that thing in the host, it’s a much higher barrier for the virus to evolve a completely new entry mechanism.”
Focusing on coronaviruses, paramyxoviruses, influenza, and enteroviruses, Heaton and his colleagues investigated changes to receptor binding proteins in host cells that could stop viruses without negatively impacting the host. “There are tons of host proteins,” Heaton said, “and we don’t have a lot of stuff that’s just hanging around for fun,” he said. Results are published in PNAS.
Instead of trying to knock something out of the host cell, Heaton said they wanted to try to add, or upregulate, something. Since the viruses they were working with were primarily respiratory viruses, he said, “We want to add things to lung that are expressed in other parts of the body but aren’t expressed in the lungs. If other cells can express these proteins, they are more likely to be safe.”
When proteins travel through the secretory pathway – the cell’s shipping and delivery system for proteins – they collect sugars, called glycans. Many pathogens, including viruses, use these glycoproteins as receptors, so Heaton and team made a list of all the proteins that can change those sugars, upregulated them one at a time in lung cells, and tested how they affect respiratory viruses.
“When we did that, we looked to see if the host cells were still happy,” Heaton said, “and were the viruses still able to bind to the cells?”
Using CRISPRa screens, they turned on genes, specifically glycan capping enzymes, which are known to alter the outer part of the sugar where the viruses bind. This allowed them to see which enzymes have the strongest effect on changing the sugars and keeping viruses out. Two stood out from the crowd: FUT1- and GAL3ST2.
When these enzymes are expressed in lungless cell lines, viral infection rate drops substantially for several different respiratory viruses.
With that success, they began testing in primary cells from a human lung grown in a dish. “These cells have air on top of them, they are making mucus, and they have cilia. They’re doing all the things lungs do,” Heaton said. Experiments using these lungs in a dish showed the same thing as the lungless cell lines – viruses couldn’t get in when FUT1- and GAL3ST2 were upregulated.
This proof of concept gets them one step closer to being able to try this out in humans, and since they are focused on what the host can do instead of the virus, the likelihood of viral mutations creating superbugs is low. “These viruses have evolved over thousands of years to be very specific, lock and key with these sugars,” Heaton said. “Now you take away these sugars and ask, can this virus to bind to something else?”
Heaton touts this as proactive research. If this becomes successful in humans, we may be able to better prepare for not just the viruses we already know about, but also other viruses that could create the next pandemic.
It’s important to note, though, that this is just the beginning. There is a lot researchers don’t know yet, like if we have these genes in our lungs and we aren’t expressing them, why? What is the cost associated with upregulated these enzymes in our lungs? What is the balancing act we need to play? And would humans even tolerate these types of manipulations?
But it’s an important first step that could help lead to fewer sick days.