The world of antiviral drug development largely operates under a simple paradigm: one bug, one drug. That is, most therapies are designed to target proteins that are unique to specific viruses, such as the COVID-19 vaccine or telaprevir for hepatitis C.
Scientists have long searched for ways to expand antivirals’ indications by attacking mechanisms that are conserved across multiple types of bugs. Now, a team of researchers from Ohio State University have identified an enzyme that when inhibited, slowed viral replication and improved outcomes in mice infected with a wide range of viruses. The results of their work were published Oct. 10 in the journal Proceedings of the National Academy of Sciences.
The targeted enzyme, NSUN2, is involved in a process that modifies RNA—called 5-methylcytosine methylation—and thereby regulating multiple biological pathways. Decades ago, scientists studying 5-methylcytosine methylation thought NSUN2 was found in viruses. However, by using newer transcriptome mapping techniques, the Ohio State researchers showed that the process takes place in mammalian cells instead. The mapping results suggested that 5-methylcytosine methylation would lead to suppression of the immune response, too.
To verify this, the researchers knocked down the gene for NSUN2 in cultured cells and human lung models. Doing so led to the production of type 1 interferon, cytokines that are vital to the innate immune response. When they tested multiple viruses against the cells—including three known for causing severe respiratory disease in humans and mice; vesicular stomatitis virus, which can cause serious disease in cattle and the herpes simplex type 1 virus—they found that viral replication and gene expression was reduced.
“If you can detect the modification, then you can study it and target it,” Chuan He, PhD, co-senior author, said in a press release. “It turns out the key here is not a viral RNA modification, but a host RNA modification, and it triggers a host immune response.”
The results held up in mice too. Knocking down the gene for NSUN2 in mice with a respiratory virus reduced the expression of viral genes and increased interferon levels. The experimental mice also had fewer lung pathologies than controls. And the same was true for vesicular stomatitis virus; normally able to kill host cells within 24 hours, the virus was almost completely wiped out in mice without the gene for NSUN2.
How does blocking NSUN2 stimulate the immune response, exactly? When the enzyme is suppressed, it exposes host RNA snippets. The innate immune system sees them as foreign invaders, unleashing a type 1 interferon response that, once it reaches a sufficient level, tackles the virus at the same time.
Next, the scientists plan to develop a drug that suppresses NSUN2’s function. They also plan to see if the same mechanism might work against another well-known foe: COVID-19.