Researchers have found a promising way to develop broad-spectrum antiviral therapies. It involves boosting a strong immune response that can stop a number of viruses in their tracks.
Experiments with cell cultures and mice demonstrated that inhibiting the activity of a particular enzyme found in all cells activates a potent innate immune response, the body’s first line of defense against external invaders. When mice were exposed to multiple types of viruses, this response drastically reduced viral particle proliferation and protected the lungs.
There are still a lot of questions to be answered, but the scientists say this could change the way antiviral drugs are made.
“Typically, in antiviral development, the saying is, ‘one bug, one drug,’” says co-senior author Jianrong Li.
“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.”
The findings were published in the Proceedings of the National Academy of Sciences.
This discovery was made possible in part by a technology that allowed the researchers to map the precise site of an RNA modification they were researching and determine which enzyme was responsible for the modification. Mapping revealed that the enzyme is responsible for a process that does not occur in viruses but rather in the mammalian hosts that viruses seek to infect.
“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,” adds co-senior author Chuan He. “It turns out the key here is not a viral RNA modification, but a host RNA modification, and it triggers a host immune response.”
Two viruses that can cause severe respiratory infections in infants and the elderly, human respiratory syncytial virus and human metapneumovirus, as well as a mouse respiratory virus called Sendai virus, the vesicular stomatitis virus found in cattle, and the herpes simplex virus, a DNA virus, were tested against the immune response in this study. When the enzyme was inhibited, replication and gene expression of all of these viruses were greatly decreased, and early evidence from prior experiments in cell cultures suggested that the SARS-CoV-2 virus may also be controlled by this antiviral method.
The RNA alteration itself, known as cytosine-5 methylation or m5C, must be modified in order to elicit an immunological response. It is one of around 170 documented chemical alterations to RNA molecules seen in living things that have an array of effects on biological processes.
Instead of specifically targeting the modification, scientists were able to prevent the RNA modification by impairing the activity of NSUN2, a crucial enzyme involved in the process. They discovered that inhibiting NSUN2 through the use of gene knockdown methods and experimental agents causes a chain reaction of cellular activity that results in robust production of type 1 interferon, one of the most effective antagonists 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,” adds co-first author Yuexiu Zhang.
It turns out that inhibiting NSUN2 in cells exposes RNA fragments that, despite being part of the host, are perceived as foreign invaders, which causes the production of type 1 interferon. Once it is present at this level, the protein will thwart viruses’ attempts to spread infection, which is the true threat.
Before discovering the effects of inhibiting NSUN2 in mice, the researchers confirmed this series of events through tests in a variety of cell types and human lung models.
To determine how the viruses behave, “we compared NSUN2-deficient mice with wild-type mice,” Li says.
“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 next step, according to the researchers, is to create a drug specifically designed to block NSUN2’s activity.
Image Credit: Getty