In the long-term battle between a herpesvirus and its human host, a University of Massachusetts virologist and her group of college students have recognized some human RNA in a position to resist the viral takeover — and the mechanism by which that happens.
This discovery, described in a paper revealed Feb. 15 in Proceedings of the National Academy of Sciences, represents an vital step within the effort to develop anti-viral drugs to combat off infections.
“This paper is about trying to understand the mechanism that makes these RNA escape degradation,” says senior creator Mandy Muller, assistant professor of microbiology. “The next step is to figure out if we can manipulate this to our advantage.”
In the Muller Lab, scholar researchers work with Muller learning how Kaposi sarcoma-associated herpesvirus (KSHV) hides for years contained in the human physique earlier than looking for to acquire management over human gene expression to full the viral an infection. At that time, folks with a weakened immune system could develop Kaposi sarcoma most cancers lesions within the mouth, pores and skin or different organs.
The researchers use genome-wide sequencing, post-transcriptional sequencing and molecular biology to look at how the human cell or the virus is aware of how to stop degradation.
“Viruses are very smart, that’s what I love to say,” Muller says. “They have tons of methods to stick round, they usually do not do quite a bit of injury for a really very long time, as a result of that is a method to cover from the immune system.
“But then, at some point — many, many years later — they reactivate. The way they do this is by triggering a massive RNA degradation event where the virus will wipe out the mRNA from the cell. That means the human system can no longer express the proteins that it needs to express, and that means also that a lot of resources are suddenly available for the virus.”
How and why some RNA are in a position to escape the viral degradation are questions Muller’s group — together with lead creator and graduate scholar Daniel Macveigh-Fierro and co-authors and undergraduates Angelina Cicerchia, Ashley Cadorette and Vasudha Sharma — has been investigating.
“We show that RNA that escape have a chemical tag on them — a post-transcriptional modification — that makes them different from the others,” Muller explains. “By having this tag, M6A, they can recruit proteins that protect them from degradation.”
Muller has been learning KSHV since she was an undergraduate in her native France, and her mission continues.
“We know you need this protein to protect the RNA from degradation, but we still don’t know how that physically stops the degradation, so that’s what we’re going to look at now,” she says.
Ultimately, understanding the mechanisms and pathways concerned in KSHV an infection could lead to the event of RNA therapeutics to deal with viral ailments.
“By identifying the determinants of what makes an mRNA either resistant or susceptible to viral-induced decay, we could use those findings to our advantage to better design anti-viral drugs and reshape the outcome of infection,” Muller says.
The analysis was supported by a $1.9 million Maximizing Investigators’ Research Award (MIRA) to Muller in 2020 from the NIH’s National Institute for General Medical Sciences.
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