A team of researchers from Stanford University and the University of California, San Francisco have developed a potential cure for the common cold and a range of other diseases.
The common cold is primarily caused by rhinoviruses, but other types of enteroviruses, coronaviruses, and adenoviruses also cause common cold symptoms. The solution is not a vaccine, which is impractical because around 200 different viruses can cause the common cold. Many also have a rapid rate of mutation. Instead, the solution is a treatment that targets a protein required by cold-causing viruses for replication. If the viruses cannot replicate inside a host, a cold will not develop.
Blocking the common cold this way makes a great deal of sense, but identifying a gene that can be targeted to block all of the above types of viruses is a major challenge.
To identify potential targets, the researchers created a culture of cells which contained groups of cells lacking one of every gene in the human genome.
The researchers then introduced a rhinovirus called RV-C15, which causes airway hyperresponsiveness in children, and an enterovirus called EV-C68, which causes acute flaccid myelitis. Some of the cells survived infection and they were analyzed to determine which gene had been taken out of action.
The two viruses are taxonomically distinct and use different host-cell proteins for replication, so the genes required to produce those proteins were also different. However, the researchers identified several genes that were required by both types of virus to invade cells, replicate, escape, and invade new cells.
Each of those genes could potentially be a target for a treatment but one in particular was particularly promising – the gene that encoded a host protein called SET domain containing 3 (SETD3) – An actin histidine methyltransferase. The protein was identified by Stanford University researchers using a genome-scale CRISPR screen.
“We identify SETD3 as critically important for viral infection by a broad panel of EVs, including rhinoviruses and non-polio EVs increasingly linked to severe neurological disease such as acute flaccid myelitis (EV-D68) and viral encephalitis (EV-A71),” wrote the researchers. “We show that cytosolic SETD3, independent of its methylation activity, is required for the RNA replication step in the viral life cycle.”
A mouse strain engineered to lack SETD3 was impervious to infection by several types of enteroviruses, including two that cause fatal encephalitis, even when the virus was injected directly into the brain. In human cells lacking SETD3 there was a 100-fold decrease in enterovirus replication and a 100-fold decrease in replication of several rhinoviruses and EV-D68, which causes acute flaccid myelitis.
In addition to serving as a possible cure for the common cold and acute flaccid myelitis, it could also protect against polio, encephalitis, myocarditis, and asthma.
Little is known about the role of SETD3 in the body, so wiping out the gene entirely to prevent generation of the protein would be unwise. However, the researchers found that the section of SETD3 used by cells for enzymatic activity is not utilized by the enteroviruses. They use a different part of SETD3 for replication, although the processes involved are not known.
“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,” said Jan Carette PhD, associate professor of microbiology and immunology at Stanford University and one of the leaders of the research study.
The study is detailed in the paper – Enterovirus pathogenesis requires the host methyltransferase SETD3 – which was recently published in the journal Nature Microbiology. DOI: 10.1038/s41564-019-0551-1