OCT 22, 2016 5:20 PM PDT

RNA Modifications Influence Viruses' Ability to Infect Cells

WRITTEN BY: Carmen Leitch
Modifications to DNA and RNA can exert a powerful influence on gene expression. The most modification to RNA, the intermediary between genes and proteins, is the methylation of the N6 position of adenosine after RNA transcription, known as N6-methyladenosine. It has been demonstrated to play a role in many varied processes such as the cellular response to stress, cancer, and circadian rhythms. New research published in Cell Host Microbe has investigated how it might influence pathogenic viruses such as the common cold, influenza and hepatitis.
RNA molecules of the hepatitis C virus carrying the N6-methyladenosine chemical tag interact with proteins that bind to this tag (green) at sites in the cells (red) that are known for virus assembly./ Credit: Nandan S. Gokhale

A research team at Duke University has shown that RNA viruses are abundantly modified with N6-methyladenosine tags. Those tags influence how viruses infect cells and by extension, human hosts. The new work focuses on the hepatitis C virus, and additionally assayed other viruses in that family like Zika, West Nile, yellow fever and dengue. The results could potentially aid in the creation of new avenues for fighting both existing and emerging dangerous viruses.
"In the case of hepatitis C, these chemical tags seem to allow the virus to establish slow, persistent infections," said the senior author of the study, Stacy M. Horner, an Assistant Professor of Molecular Genetics and Microbiology at Duke University School of Medicine.

"But the other viruses harbor different patterns of N6-methyladenosine tags, suggesting that the modifications may be regulating these viruses in different ways," Horner continued. "We're interested in figuring out how the N6-methyladenosine modification might regulate infection in other viruses and also how it might affect the host's response to infection. That would give us new targets for antiviral drug development."

While it’s been known for some time that methyl, acetyl and phosphate functional groups were often attached to RNA, their purpose was a mystery. Researchers have been aided by tremendous advances in sequencing technologies in recent years that have allowed for the detection and study of genetic modifications. Horner and others have shown that such alterations can aid in the stability of the human immunodeficiency virus, which replicates inside the nucleus of cells.
A chemical tag on the RNA of the hepatitis C virus called N6-methyladenosine (m6A) has been found to slow the production of new viruses. A protein called YTHDF that binds to m6A is known to congregate around the lipid droplets where viral particles are manufactured, slowing the production of new viruses. /Credit: Duke University
The graphical abstract for this work is shown above. Horner studied the effect of the N6-methyladenosine tag on viruses that replicate not in the nucleus, but in the cytoplasm of the cell. Those viruses are in the Flaviviridae viral family and are primarily spread via ticks and mosquitoes. The research team utilized cutting edge sequencing techniques in collaboration with XXXX to map the N6-methyladenosine modifications present on the genome of the hepatitis C virus genome. In total,19 different regions of the viral RNA were modified.
A graduate student, Nandan S. Gokhale, set to work mutating each of the modified regions to inactivate the modifications. That allowed the researchers to decipher which viral life stage was impacted by the changes. The team found that N6-methyladenosine slowed down viral particle packaging. Such a modification could prevent a virus like hepatitis C from decimating its target organ, the liver, and instead allows a slow infection to set in that doesn’t cause an overwhelming response from the immune system.
The researchers went on to map the locations of N6-methyladenosine modifications in the other viruses in the study. The work will hopefully inform future research into these viruses; treatment would benefit from a deeper characterization.
"One thing we can speculate about is that these modifications might regulate the Zika virus life cycle," explained Gokhale. "We found that the profiles of N6-methyladenosine in different strains of Zika that have different levels of pathogenicity are strikingly different. The African strain has one pattern, whereas the Puerto Rican strain, which is closely related to the Brazilian strain that is associated with microcephaly, has another. While we don't understand what that means yet, these different distributions of RNA modifications could differentially regulate these viruses."
Sources: Phys.org via Duke University, Cell Host Microbe
About the Author
Bachelor's (BA/BS/Other)
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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