Roughly aware of an epigenetic change known as N6-methyladenosine modification (also known as m6A ) that can be seen in RNA, Li and his team wanted to see if HMPV has this modification, and how it drives the virus’ effects.
How was the methylation studied and its effects characterized?
Using high-throughput sequencing, Li scanned the virus’ genes and identified which one contains the greatest extent of m6A methylation before then knocking out these modifications to make a mutant virus. Looking at how these mutant viruses performed would shed light on the impact of m6A methylation.
When human cells were exposed to the knock-out virus, they produced an antiviral protein known as type I interferon that pointed to the activation of the innate immune response, or the somewhat generalized response that the body has to a foreign pathogen. According to Li, “This opened up a big question. Why would a virus lacking this methylation produce a much higher innate immune response?”
Upon reviewing the cellular signaling pathways involved, it became evident that m6A methylation makes the virus able to hide from the immune system by masking the RNA so that it didn’t stand out as being different than the host RNA. The immune system therefore doesn’t recognize the virus as being non-self RNA, and so it doesn’t summon the innate immune response—meaning that the virus is able to persist, undetected.
It’s possible that other viruses use this same methylation trick to escape recognition; that will have to be further characterized. But, in the meantime, how could this discovery be used to develop something that could reduce the number of HMPV infections?
Anti-HMPV vaccine potential looks promising
Li and his team used cotton rats as their experimental model to see if targeting the m6A methylation could lead to a vaccine. One group of rats was given a placebo, while the other rats was given the mutant virus. The latter not only had an innate immune response, but also produced the sort of pathogen-specific adaptive immune response that would protect them specifically from HMPV. The rats had total protection from the virus throughout their respiratory tract.
“In the case of cotton rats, the mutant virus produced a higher amount of type I interferon, and triggered a higher antibody response and a higher T-cell immune response. That means you’ve triggered higher protective ability against the virus infection. So mutating the virus enhances vaccine efficacy,” Li noted. “That is exactly what we want.”
Not only do Li’s team’s findings point toward a potential target (the methylation modification) that can be leveraged in the development of a specifically anti-HMPV vaccine, but it also opens the door for vaccine development against other viruses.
HPMV is actually part of the same family of viruses as respiratory syncytial virus (RSV), which is the number one cause of respiratory infections. “This [HPMV finding] is exciting because RSV was discovered in 1953, but we still don’t have a vaccine,” said Li.
And so, aside from the steps needed to further develop and validate an anti-HMPV vaccine, Li’s research findings can be applied to other viruses—like RSV—in hopes of developing effective vaccines.
Source: Li J. et al. (2020). N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I. Nature Microbiology
Reference: Emily Caldwell “Exposing a virus’s hiding place reveals new potential vaccine” Ohio State News 03 Feb. 2020. Web.