Researchers have found that viruses causing human respiratory infections called human metapneumovirus (HMPV) have a special ability to hide itself from the body’s immune system. This prevents the body from fighting the infection off. This very strategy has been used in development of a vaccine against HMPV say the researchers. A new study on this was published in the latest issue of the journal Nature Microbiology today.
Image Credit: PhotobyTawat / Shutterstock
The HMPV virus – a member of the respiratory syncitial virus (RSV) family, was discovered in 2001 explained the researchers and it has been shown to be around for around five decades before that. This virus has been shown to cause deadly respiratory tract infections among the humans it infects. In fact, at present, this virus is known to be the second most common respiratory tract infection causing virus in humans. The infection can prove to be fatal for elderly and infants explained the researchers. RSV infections are common in infants and are one of the leading causes of chest infections in infants and elderly population across the world. At present there are no vaccines against RSV, explained the researchers and tens of thousands die each year due to this infection. If a potential vaccine could be developed against HMPV, they explain, vaccines could also be developed against RSV.
Professor of virology in The Ohio State University Department of Veterinary Biosciences Jianrong Li, also senior author of the study said in a statement, “This is exciting because RSV was discovered in 1953, but we still don't have a vaccine. The virus inhibits the innate immune response, and can infect the same person again and again.” Li is also a member of Ohio State's Infectious Diseases Institute. Li added, “Now we have a mutant strain of HMPV that can trigger a higher immune response. Right now we're working to translate this same concept to see if it can work for RSV, too.”
The team found that the HMPV has a modification on its RNA or genetic code that helps it to hide from the natural immune system of the human body. This natural or innate immunity is one of the first defences against the infectious agents that invade the body. When the virus hides from the immune system, it goes on to infect the host cells which it utilizes to make new virus particles and thus the infection becomes full blown. For this study the team blocked the RNA modification that virus was performing to escape the immunity. This led to a stronger innate immune response against the virus and thus successfully eliminated it from the body.
In the 1970s the researchers had found that certain viruses underwent a RNA modification in order to survive the immune response. This RNA modification is called N6-methyladenosine modification, wrote the researchers. This chemistry has not been clearly understood till now say the researchers and this process became the key to development of the vaccine they said. The RNA modification is a form of “epigenetic methylation”, they wrote.
For testing this theory the team used lab cotton rats to show that the mutated virus lost its virulence and became a vaccine of sorts against HMPV infections. It could help trigger an innate immune response which could fight incoming HMPV infections. Since both HMPV and RSV belong to the same family, this novel vaccine could help fight RSV as well explained the researchers.
The team looked at the effects of RNA modification called the m6A methylation on the HMPV and found that its blockade had an effect on the virulence of the virus. They screened a selection of viruses to isolate the genes that contained the most m6A methylation. To do this they used high-throughput sequencing. In these areas, the team mutated the gene and blocked the RNA modification. Now they studied the effect of the viruses without these modifications. They were introduced into human cells and the viruses stimulated production of a protein called the type I interferon. Interferons are activated when the immune system is activated and these are basically antiviral in nature. Thus, high levels of type 1 interferon meant that the immune system was no activated and capable of fighting the viruses. Li said, “This opened up a big question. Why would a virus lacking this methylation produce a much higher innate immune response?” Looking back at the whole process, the team found out the RNA modification behind the viral survival.
Li explained, “We know that when a virus infects cells, it produces RNA, and human cells in the innate response try to separate self-RNA and nonself-RNA. The virus is smart: It gained this methylation, and now our host innate response is confused. That's how the virus escapes recognition by the innate immune response.” Mijia Lu, the first author of the study, who is also a postdoctoral researcher in Li's laboratory said, “We are very excited about this finding. This novel function of m6A may also be conserved in many viruses.”
As of now the team has filed for a patent to develop this concept for development of a vaccine against HMPV and RSV. Their study was supported by the National Institutes of Health (NIH).
Lu, M., Zhang, Z., Xue, M. et al. N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I. Nat Microbiol (2020). https://doi.org/10.1038/s41564-019-0653-9