A new study finds a promising approach toward developing broad-spectrum antiviral therapies

Stimulating immune response.
Mert Erdemir
Scanning electron micrograph of human respiratory syncytial virus.
Scanning electron micrograph of human respiratory syncytial virus.

National Institute of Allergy and Infectious Diseases 

A new study conducted by the Ohio State University researchers has revealed a promising approach toward the development of broad-spectrum antiviral treatments that functions by stimulating a strong immune response capable of stopping the infection of several viruses, according to a press release published by the institution.

In their experiments on cell cultures and mice, researchers have proved that thwarting a specific enzyme present in all cells triggers a powerful innate immune response. This has also been challenged by several types of viruses and appeared to lower the replication of viral particles dramatically and protect mouse lungs.

“Typically, in antiviral development, the saying is, ‘one bug, one drug,’” said Jianrong Li, co-senior author of the study and a professor of virology in The Ohio State University Department of Veterinary Biosciences and Infectious Diseases Institute.

“A drug that can stimulate the immune system to have broad antiviral activities would be very attractive – one drug against multiple bugs would be an ideal situation.”

Triggering the host's immune response.

This discovery was partly made by a method the researchers used to map the exact location of an RNA modification and to identify the enzyme that made the alteration. The mapping enabled them to deduce that this enzyme functions not in viruses but in mammals that were targeted by viruses.

“If you can detect the modification, then you can study it and target it. But it took a while to figure this out – in the beginning of the pandemic, a lot of people, including our lab, were studying RNA modifications in hosts and viruses,” said co-senior author Chuan He, John T. Wilson Distinguished Service Professor of chemistry, biochemistry and molecular biology at the University of Chicago.

“It turns out the key here is not a viral RNA modification, but a host RNA modification, and it triggers a host immune response.”

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Blocking an enzyme

The testing process of the approach included two viruses, the human respiratory syncytial virus and human metapneumovirus that can possibly cause severe respiratory infections in infants and the elderly, in addition to a mouse respiratory virus called Sendai virus, the vesicular stomatitis virus found in cattle, and the herpes simplex virus.

When the enzyme was blocked, all of these viruses' ability to replicate and gene expression was also greatly diminished. As per preliminary data from earlier studies, the SARS-CoV-2 virus could be controlled similarly with this antiviral approach.

In order to start the immune system response, the RNA modification itself must be altered. In this direction, researchers blocked the function of an essential enzyme called NSUN2 and discovered that inhibiting NSUN2 through gene knockdown techniques and experimental agents causes a chain reaction of cellular activity that results in a strong production of type 1 interferon, one of the most powerful fighters in the innate antiviral response.

“Amazingly, blockage of NSUN2 almost completely shuts down the replication of vesicular stomatitis virus, a model virus that normally kills the host cells within 24 hours and replicates to a very high titer, and strongly inhibits both RNA and DNA viruses,” said the study co-first author Yuexiu Zhang, a Ph.D. student in Li’s lab.

It turns out that inhibiting NSUN2 causes cells to become exposed to RNA fragments that, although being part of the host, are seen as foreign invaders, triggering type 1 interferon production. The protein will thwart viruses' attempts to infect people once it is present at this high level.

“We compared NSUN2-deficient mice with wild-type mice to see how the viruses act,” Li said. “Once we inhibited NSUN2, viral replication in the lung decreased and there was less pathology in the lung, and that correlated with enhanced type 1 interferon production."

“This finding in mice and our other experiments proved that NSUN2 is a druggable target.”

The study is published in the journal Proceedings of the National Academy of Sciences.

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