A newly discovered protein can permanently relieve us of a cold
Virus protection is one of the most acute problems in medicine. The invention of vaccines was a big step forward, but they can still only repel some of the known viral attacks. They work by “teaching” our immune system to recognize a specific virus so that it can develop an effective immune response if it detects the same “invader” in the future.
Another approach is the use of antiviral drugs that prevent the growth of viruses and can be used to quickly treat current infections. However, the development of safe antiviral drugs is difficult because viruses capture the carrier’s own cellular apparatus in order to multiply, so interference can also harm human cells.
The problem with both approaches is the huge variety of viral pathogens. For example, the viral group responsible for at least half of all colds — rhinoviruses — has at least 160 different subtypes. The development of more than 100 vaccines for the treatment of one disease is obviously impractical, and those that are, of course, are not enough, so the cold continues to flourish.
The situation is complicated by the fact that many viruses can mutate in such a way that they become resistant to drugs or able to withstand acquired immunity. That is why an important goal in virology is the development of broad-spectrum antiviral drugs effective simultaneously against many viruses.
In a study published Monday in Nature Microbiology, microbiologist Jan Carett of Stanford University and colleagues report that they found a human gene that produces the protein necessary for the functioning of numerous enteroviruses, including rhinoviruses. Experiments on human and mouse cells have shown that a number of enteroviruses cannot reproduce without this protein.
This beautiful ball is a rhinovirus.
This work can pave the way for the development of antiviral drugs that are effective against many diseases, including most colds, and shed light on how viruses use their carrier’s cellular material. Carett and colleagues “accomplished a feat to find this gene and characterize it,” says Ann Palmenberg, a virologist at the University of Wisconsin-Madison, who provided some advice and materials for the study, but did not directly participate in it. “This is a wonderful job.”
Enteroviruses also include poliovirus, Coxsackie virus (which causes myocarditis or inflammation of the heart) and EV-D68, a virus associated with acute flaccid myelitis. To search for similarities between these viruses, the researchers used advanced gene editing technology to inactivate (partially or completely disable. approx. perev.) individual genes in human cells grown in a laboratory environment.
First, they created a bank of cells, in each of which there was no separate gene covering the entire human genome in total. They then infected these cells with two enteroviruses: EV-D68 and rhinovirus type C, called RV-C15. The latter is a relatively recently discovered type of rhinovirus that can seriously aggravate asthma symptoms and increase the risk of developing asthma and chronic obstructive pulmonary disease in infected children. Although they are both enteroviruses, EV-D68 and RV-C15 are fairly distant relatives who primarily use various host cell proteins.
After that, the team examined which genes were absent in cells that continued to thrive after infection, focusing on those few in which the lack of genes interfered with both viruses. In addition to the two genes that produce the proteins that enteroviruses have already known are needed, another little known thing has emerged: SETD3, which creates a protein of the same name.
The SETD3 gene in the human genome is located on the 14th chromosome at the 14q32.2 locus (highlighted in red).
Carett and colleagues then examined how broadly enteroviruses are generally dependent on SETD3 protein. They created cells lacking SETD3 and infected them with seven viruses representing different types of human enteroviruses: all three types of rhinoviruses (A, B and C), poliovirus, two types of Coxsackie virus and EV-D68. None of them could thrive in cells with SETD3 deficiency. their reproduction rate was reduced by 1000 times compared to control cells that possessed this gene.
“We could barely detect any virus multiplying in knocked out cells,” Carett says, referring to cells designed to not have this gene. The findings suggest that the use of SETD3 can lead to a widely effective therapeutic agent. “We really tried to maximize the variety of enteroviruses we tested, and [SETD3] was important to all of them; it was amazing, ”says Carett. “I would be surprised if there are enteroviruses that do not need this protein in carrier cells.”
This experiment was carried out on special cancer cells widely used in experiments, but the team repeated some tests on the type of cells that are located at the entrance to the lungs and obtained equally impressive results. “For respiratory viruses such as rhinovirus and EV-D68, the main medium is bronchial epithelial cells, because that is where the virus actually multiplies,” says Carett.
Finally, Carett and his team genetically modified the mice, depriving them of the SETD3 gene. “To our great surprise, if you make mice that lack SETD3 protein, then they turn out to be quite viable and apparently healthy,” he says. Alas, they still found a fatal flaw: such mice hardly gave birth.
In a recent study, biologist Or Gozani, who also worked at Stanford and co-authored a new study, found with colleagues that in a process called methylation, the SETD3 protein modifies actin, a protein that is important for cell division and also for muscle contraction. “Actin methylation seems to be important for smooth muscle contraction during childbirth,” Carett says. He and his colleagues injected two enteroviruses into these mice. the Coxsackie virus and EV-A71, both of which cause a fatal neurological disease for them, including paralysis and inflammation of the brain. Mice without the SETD3 gene were immune to both viruses.
Researchers then tried to determine why viruses need SETD3 protein. They “forgot” for a while about his usual role (actin change), hoping that in the future it could be modified so as not to interfere with this function. In addition, they narrowed the spectrum of observations to reproduction. Viruses use a combination of their own components and parts that they extract from the cell to create a “replication complex” that acts like a copy machine. “The virus enters the cell, but cannot begin to copy itself,” says Carett. “SETD3 is an integral part of this copier.”
This is how the SETD3 protein looks structurally.
There are two possibilities: either viruses use SETD3 in a unique way, or they use the still unknown SETD3 function. The latter possibility means that drugs targeted at SETD3 may have unforeseen side effects. “We have a long way to go before we find out if we can develop an antiviral drug aimed at using this protein; it’s many years of work, ”says microbiologist Vincent Racaniello from Columbia University, who did not participate in the new study. "The fact that he works on mice, generally speaking, does not mean that everything will be fine with people."
So far, the only way to accurately determine whether a drug aimed at using SETD3 is harmful to humans is to test it in a small human trial. “And if so, then for now this is the end of the story,” says Racanelio. "It really tempers my enthusiasm."
According to Palmenberg, knowing why viruses use SETD3 will largely determine the ways to create effective therapy. It will answer such important questions as, for example, which part of SETD3 needs to be blocked in order to stop virus replication, and whether this applies to most enteroviruses at the same time. This information will determine how the medicine will look, how it will be delivered, and whether it will even be possible. “We just don’t understand all this yet, because we don’t yet know why [the virus] binds to this protein in the first place,” says Palmenberg.
In addition to addressing such issues, the Caretta team plans to look for chemicals that either stop the interaction of enteroviruses with SETD3 or break down this protein. “We have a goal, but no medicine yet,” he says. "Now we are focused on him." Ultimately, he and his colleagues hope to get around the problem of viruses that develop resistance to vaccines.
Traditional antiviral agents target viral proteins, which allows viruses to mutate relatively easily. “We do this a little more carefully, targeting the carrier proteins, so it will be much harder for the virus to get around the effect of the drug,” Carett says. This approach is known as host-directed therapy, because treatment modifies something in the cells of the host, which prevents the virus from functioning normally. “This therapy has wide potential and is less likely to develop antiviral drug resistance,” Carett says. “There is real enthusiasm for this approach.”