Researchers have discovered a cellular mechanism that can stop viruses from spreading the common cold and other infections, such as the debilitating polio-like illness, acute flaccid myelitis. Reporting their findings in Nature Microbiology, a team led by scientists at Stanford University and the University of California-San Francisco showed that disabling a single protein could prevent a range of enteroviruses—including rhinoviruses—from replicating and spreading. Rhinovirus infections represent about half of all common colds. “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?’” said Jan Carette, PhD, one of the study’s senior authors and associate professor of microbiology and immunology, Stanford School of Medicine, Stanford, CA. “Now we have a new way to do that.” The researchers demonstrated the effect in human cell lines and in mice, which became resilient not only to enteroviruses that cause common colds, but also those that lead to myocarditis, poliomyelitis, acute flaccid myelitis, and hand-foot-and-mouth disease. The missing protein The main barrier to curing the common cold is that there is no single virus responsible. In fact, about 160 known rhinoviruses exist. Viruses work by hijacking cells and taking over their functions, enabling them to replicate quickly and spread. They’re also quick to mutate, helping them become resistant to drugs as well as eluding scientists’ surveillance. So, rather than trying to tackle the myriad of viruses individually, these investigators looked instead for proteins that the enteroviruses might have in common—particularly proteins involved in viral replication. To do so, they created a human cell line that was designed to be susceptible to two particular enteroviruses—RV-C15, which leads to severe childhood asthma, and EV-D68, the virus linked to acute flaccid myelitis. Then, the researchers performed CRISPR–Cas9 gene editing to knock out one different gene in each cell, such that the cell line as a whole was missing one of every gene in the human genome. The researchers then infected the cells with RV-C15 and EV-D68 viruses. Upon analyzing the results, the investigators found one gene that encoded a protein—SETD3—that was critically necessary for both viruses. To verify this finding, the researchers created a human cell line in which they genetically deleted the SETD3 gene. When the investigators infected these cells with enteroviruses—including RV-C15 and EV-D68, as well as viruses responsible for myocarditis, poliomyelitis, and hand-foot-and-mouth disease—the viruses didn’t replicate. Compared with regular human cells, the human cells without SETD3 had more than a 1,000-fold reduction in viral RNA accumulation. The researchers also specifically tested human bronchial epithelial cells in which SETD3 was deleted. When infected with common cold-type rhinoviruses and EV-D68 strains, the cells had about a 100-fold reduction in viral RNA accumulation compared with regular bronchial epithelial cells. Knocked out cold Finally, the investigators tested mice that were genetically bred without SETD3—the lack of which didn’t appear to affect their growth, development, or ability to reproduce. When these mice were injected with viruses that cause encephalitis, acute flaccid myelitis, and hand-foot-and-mouth disease, none developed infection. “In contrast to normal mice, the SETD3-deficient mice were completely unaffected by the virus,” Dr. Carette said. “It was the virus that was dead in the water, not the mouse.” These results suggest that drugs that inhibit the SETD3 protein could prevent the replication and spread of illness-inducing enteroviruses in the host. “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,” Dr. Carette predicted. Source
