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Scientists say they have proposed a promising strategy for the development of broad-spectrum antiviral therapies that promote a robust immune response capable of stopping the trajectory
of infection in many viruses.
Cell culture and mouse experiments have shown that blocking the function of a particular enzyme present in all cells triggers a powerful innate immune response
.
This response significantly reduced the replication of viral particles and protected the mice from injury
.
There are still multiple avenues to be explored, but scientists believe the discovery could help change the way antiviral drugs are developed
.
"Typically, in antiviral drug development, as the saying goes, 'One virus, one drug,'" said
Jianrong Li, Ph.
D.
, co-senior author of the study and professor of virology in the Department of Veterinary Biosciences at The Ohio State University and the Institute of Infectious Diseases.
"A drug that stimulates the immune system with broad antiviral activity would be very attractive – one drug against multiple bacteria would be an ideal situation
.
"
"5-Methylcytosine (m5C) is a common RNA methylation
.
However, its biological function remains a mystery
.
Here, we found that the deletion of the m5C methyltransferase NSUN2 leads to an enhanced type I interferon (IFN) reaction, which significantly inhibits the replication of large amounts of RNA and DNA viruses in vitro," the researchers wrote
in the PNAS paper.
Notably, this M5C-mediated antiviral innate immunity also remains conserved
in in vivo mouse models.
Mechanically, deletion of m5C methyltransferase reduces host RNA m5C methyl group and enhances noncoding RNA transcribed by polymerase III that can be recognized by RIG-I, triggering enhanced type I IFN signaling
.
"Our study reveals a novel role for m5C in regulating innate immunity and highlights m5C as a new target for
the development of broad-spectrum antiviral therapies.
"
Part of the reason for this finding is that the researchers used a technique to map the precise location of the RNA modifications they were studying and see which enzymes made the modifications
.
This map allowed them to determine that the enzyme's role did not occur in the virus, but in
the mammalian host that the virus wanted to infect.
"If you can detect that change, then you can study it and target it
.
" But it will take a while to figure it out — at the start of the pandemic, a lot of people, including our lab, were studying RNA modifications in hosts and viruses," said
senior co-author Chuan He, Ph.
D.
, a professor of chemistry at the University of Chicago.
"It turns out that the key here is not viral RNA modification, but host RNA modification, which triggers the host immune response
.
"
In this study, viruses tested for immune responses included two viruses that can cause severe respiratory infections in infants and the elderly (human respiratory syncytial virus and human metapneumovirus), as well as a murine respiratory virus called Sendai virus, vesicular stomatitis virus and herpes simplex virus
found in cattle.
When this enzyme is blocked, replication and gene expression of all these viruses are significantly reduced
.
Preliminary data from early cell culture studies suggest that this antiviral strategy can similarly control the SARS-CoV-2 virus
, the researchers said.
The RNA modification itself, known as cytosine-5 methylation, or m5C, is actually what is needed to trigger an
immune system response.
It is one of about 170 known chemical modifications on RNA molecules in living organisms that can affect biological processes
in a variety of ways.
Instead of targeting modifications
, the researchers could block changes in RNA by inhibiting the function of a key enzyme called NSUN2 in this process.
They found that inhibiting NSUN2 using knockout techniques and experimental agents triggered a cascade of cellular activity, leading to a robust production of type 1 interferon, one of
the most powerful fighters in the innate antiviral response.
"Surprisingly, blocking NSUN2 almost completely turned off the replication of the vesicular stomatitis virus, a model virus that typically kills host cells within 24 hours, replicates to very high titers, and strongly inhibits RNA and DNA viruses," said
Yuexiu Zhang, co-first author of the study.
It turns out that blocking the function of NSUN2 within cells exposes RNA fragments that, although belonging to the host, are considered foreign invaders, triggering the production
of type 1 interferon.
Once this protein reaches such high levels, it stops the real threat: the virus trying to cause the
infection.
Before looking at blocking the effects of NSUN2 on mice, the researchers validated this sequence of events
in experiments on multiple types of cells and human lung models.
"We compared mice lacking NSUN2 with wild-type mice to see how the virus functioned, and once we inhibited NSUN2, there was less viral replication in the lungs and less pathology in the lungs, which was associated with
enhanced type 1 interferon production.
" This discovery in mice and our other experiments demonstrate that NSUN2 is a druggable target
.
”
The next step, the researchers say, involves developing a drug
that specifically inhibits NSUN2 function.
