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RNA modification – a viral hideout

Scientists show how human metapneumonia (hMPV) virus exploits RNA modification to prevent host differentiation of self and non-self RNA, thereby evading an innate immune response. This mechanism could serve as a hMPV vaccine target, and potentially more if found to be well-conserved.

Researchers at Ohio State University used hMPV study to show how it’s able to avoid immune detection. Whilst only discovered in 2001, the paramyxovirus is recognised as the leading cause of acute respiratory disease in children, and the elderly also tend to be particularly susceptible. hMPV belongs to the same family as the even more common Respiratory Syncytial Virus (RSV), meaning the research might hold the potential for a multi-functional vaccine.

Zhang et al., studied an epigenetic methylation of RNA called N6 – methyladenosine (m6A) that is biologically common but it’s function is poorly understood. It had been hypothesised that the mechanism might be a survival mechanism that viruses evolved to avoid detection from their host.

Through high-throughput sequencing, the team identified which viral genes exhibited the highest levels of m6A methylation and subsequently demonstrated how over-expression of these genes resulted in increased viral protein expression and replication.

Conversely, they generated recombinant viruses that lacked m6A sites, without changing the amino acids that they encoded, to demonstrate how reduced methylation affected the host immune response. RNA-seq analysis showed that the mutated m6A sites caused an increase in an important anti-viral protein called type 1 interferon (IFN-1). This meant that the virus lacking this methylation produced a higher than expected immune response.

Furthermore, the researchers demonstrated how the mutated hMPV strain when used as a vaccine in cotton rats promoted both the innate and adaptive immune response. As IFN-1 triggered enhanced levels of antibodies and T-cells in rats, the work showed how targeting m6A methylation could make an efficacious vaccine. The researchers have begun a patent application for their concept in the development of a live attenuated vaccine for HMPV and RSV.

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