Discovery of protective RNA mechanism informs further development of antiviral drugs

In the long-term battle between a herpesvirus and its human host, a University of Massachusetts virologist and her team of students have identified a human RNA capable of resisting viral takeover – and the mechanism by which this happens. product.

This discovery, described in an article published on February 15 in Proceedings of the National Academy of Sciencesrepresents an important step in the effort to develop antiviral drugs to fight infections.

“This article aims to try to understand the mechanism that makes these RNAs escape degradation,” says lead author Mandy Muller, assistant professor of microbiology. “The next step is to determine if we can manipulate this to our advantage.”

In the Muller Lab, research students are working with Muller to study how the Kaposi’s sarcoma-associated herpes virus (KSHV) hides for years inside the human body before seeking to control gene expression humans to complete viral infection. At this point, people with weakened immune systems may develop cancerous lesions of Kaposi’s sarcoma in the mouth, skin, or other organs.

Researchers use genome-wide sequencing, post-transcriptional sequencing and molecular biology to examine how the human cell or virus knows how to prevent degradation.

“Viruses are very smart, that’s what I like to say,” says Muller. “They have a lot of strategies to stick around, and they don’t do a lot of damage for very long, because it’s a way of hiding from the immune system.

“But then at some point – many years later – they reactivate. The way they do this is to trigger a massive RNA degradation event where the virus will remove the mRNA from the cell. This means that the human system can no longer express the proteins it needs to express itself, and that also means that a lot of resources are suddenly available to the virus.”

How and why certain RNAs are able to evade viral degradation are questions that Muller’s team – comprising lead author and graduate student Daniel Macveigh-Fierro and co-authors and undergraduate student Angelina Cicerchia, Ashley Cadorette and Vasudha Sharma – investigated.

“We show that the escaped RNAs carry a chemical tag – a post-transcriptional modification – that makes them different from others,” says Muller. “By having this label, Mr.6A, they can recruit proteins that protect them from degradation.”

Muller has studied KSHV since she was a student in her native France, and her mission continues.

“We know you need this protein to protect RNA from degradation, but we still don’t know how it physically stops degradation, so that’s what we’re going to look at now,” she says.

Ultimately, understanding the mechanisms and pathways involved in KSHV infection could lead to the development of RNA-based therapies to treat viral diseases.

“By identifying the determinants of what makes an mRNA resistant or susceptible to viral decay, we could use these findings to our advantage to better design antiviral drugs and reshape the outcome of infection,” Muller said.

The research was supported by a $1.9 million Maximizing Investigators’ Research Award (MIRA) awarded to Muller in 2020 by the NIH’s National Institute of General Medical Sciences.

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Material provided by University of Massachusetts at Amherst. Note: Content may be edited for style and length.

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