Researchers have uncovered a viable technique for the development of broad-spectrum antiviral treatments that focuses on building a robust immune response capable of halting the spread of several viruses.
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 defence 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 number of avenues to investigate, but the experts believe this discovery could alter the strategy for producing antiviral drugs.
Typically, in antiviral medication research, the adage “one virus, one drug” applies. A medicine that can boost the immune system to have wide antiviral effects would be highly desirable; it would be ideal if a single drug could combat multiple pathogens.
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 led them to conclude that this enzyme is not active in viruses, but rather in the mammalian hosts that viruses seek to infect.
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 over 170 known chemical changes on RNA molecules in living organisms that influence a number of biological processes.
Instead of targeting the alteration, researchers were able to stop the RNA change by inhibiting the action of a critical enzyme in the process, NSUN2. Using gene knockdown techniques and experimental agents, scientists discovered that inhibiting NSUN2 triggers a cascade of cellular actions that results in the robust production of type 1 interferon, one of the most effective antiviral proteins.
It has been discovered that inhibiting NSUN2’s function in cells exposes RNA fragments that, despite belonging to the host, are perceived as foreign invaders, triggering the production of type 1 interferon. Once available at this level, the protein will thwart the true threat, which consists of infecting viruses.
Before discovering the effects of inhibiting NSUN2 in mice, the researchers confirmed this sequence of events in studies with multiple cell types and human lung models.
Next steps include the development of a medication tailored to inhibit NSUN2’s function, according to the researchers.
Zhang, Y., et al. (2022) 5-methylcytosine (m5C) RNA modification controls the innate immune response to virus infection by regulating type I interferons. PNAS.