Temporarily disabling a single protein inside our cells might be able to protect us from the common cold and other viral diseases, according to a new study.
“Our grandmas have always been asking us, ‘If you’re so smart, why haven’t you come up with a cure for the common cold?'” says Jan Carette, associate professor of microbiology and immunology at Stanford University. “Now we have a new way to do that.”
Researchers made the findings in human cell cultures and in mice. The approach of targeting proteins in our own cells also worked to stop viruses associated with asthma, encephalitis, and polio.
Colds, or noninfluenza-related upper respiratory infections, are for the most part a weeklong nuisance. They’re also the world’s most common infectious illness, costing the United States economy an estimated $40 billion a year.
At least half of all colds are the result of rhinovirus infections. There are roughly 160 known types of rhinovirus, which helps to explain why getting a common cold doesn’t stop you from getting another one a month later. Making matters worse, rhinoviruses are highly mutation-prone and, as a result, quick to develop drug resistance, and to evade the immune surveillance previous exposure or a vaccine brings about.
As reported in Nature Microbiology, Carette and his associates found a way to stop a broad range of enteroviruses, including rhinoviruses, from replicating inside human cells in culture, as well as in mice. To accomplish this feat, they disabled a protein in mammalian cells that all enteroviruses appear to need in order to replicate.
Survivor cells
Poliovirus is one of the most well-known and feared enteroviruses. Until the advent of an effective vaccine in the 1950s, the virus spelled paralysis and death for many thousands of children each year in the United States alone.
Since 2014, research has implicated another type of enterovirus, EV-D68, in puzzling biennial bursts of a polio-like disease, acute flaccid myelitis, in the United States and Europe. Other enteroviruses can cause encephalitis and myocarditis—inflammation of the brain and the heart, respectively.
Like all viruses, enteroviruses travel lightly. To replicate, they take advantage of proteins in the cells they infect.
To see what proteins in human cells are crucial to enteroviral fecundity, the investigators used a genome-wide screen developed in Carette’s lab. They generated a cultured line of human cells that enteroviruses could infect. The researchers then used gene editing to randomly disable a single gene in each of the cells. The resulting culture contained, in the aggregate, cells lacking one or another of every gene in our genome.
The scientists infected the culture with RV-C15, a rhinovirus known to exacerbate asthma in children, and then with EV-C68, implicated in acute flaccid myelitis. In each case, some cells managed to survive infection and spawn colonies.
“It was the virus that was dead in the water, not the mouse.”
The scientists could then determine which genes were knocked out of commission in each colony. While both RV-C15 and EV-D68 are enteroviruses, they’re taxonomically distinct and require different host-cell proteins to execute their replication strategies. So, most of the human genes encoding the proteins each viral type needed to thrive were different, too.
But there were only a handful of individual genes whose absence stifled both types’ ability to get inside cells, replicate, bust out of their cellular hotel rooms, and invade new cells. One of these genes in particular stood out. This gene encodes an enzyme called SETD3. “It was clearly essential to viral success, but not much was known about it,” Carette says.
Immune to infection
The scientists generated a culture of human cells lacking SETD3 and tried infecting them with several different kinds of enterovirus—EV-D68, poliovirus, three different types of rhinovirus, and two varieties of coxsackievirus, which can cause myocarditis. None of these viruses could replicate in the SETD3-deficient cells, although all proved capable of pillaging cells with restored SETD3-producing capability.
The researchers observed a 1,000-fold reduction in a measure of viral replication inside human cells lacking SETD3, compared with controls. Knocking out SETD3 function in human bronchial epithelial cells infected with various rhinoviruses or with EV-D68 cut replication about 100-fold.
Mice bioengineered to completely lack SETD3 grew to apparently healthy fertile adulthood and remained impervious to infection by two distinct enteroviruses that can cause paralytic and fatal encephalitis, even when the researchers injected these viruses directly into the mice’s brains soon after they were newly born.
“In contrast to normal mice, the SETD3-deficient mice were completely unaffected by the virus,” Carette says. “It was the virus that was dead in the water, not the mouse.”
Enteroviruses, the scientists learned, have no use for the section of SETD3 that cells employ for routine enzymatic activity. Instead, enteroviruses cart around a protein whose interaction with a different part of the SETD3 molecule, in some as yet unknown way, is necessary for their replication.
“This gives us hope that we can develop a drug with broad antiviral activity against not only the common cold but maybe all enteroviruses, without even disturbing SETD3’s regular function in our cells,” Carette says.
Additional coauthors are from Stanford; the University of California, San Francisco; Chan Zuckerberg Biohub; and the VA Palo Alto Health Care System.
Source: Stanford University
