UC Irvine Researchers Develop Innovative CRISPR-Cas9 Method to Understand Antiviral Defense Response

Researchers from the University of California, Irvine have developed a new, unbiased method utilizing CRISPR-Cas9 technology to identify novel regulators of the human antiviral defense response. This advancement is pivotal for the development of new antiviral therapies.

The study, published online today in the journal Proceedings of the National Academy of Sciences, details how researchers identified the transcription factor IRF2 as a critical regulator of the OAS3-RNase L pathway. This pathway, activated following RNA virus infection, plays a vital role in suppressing viral replication by cleaving viral genomes.

The team’s new method, called CRISPR-Translate, leverages CRISPR-Cas9 technology to identify novel regulators of the antiviral defense response. This approach can also be adapted to investigate other key defense pathways that prevent viral replication and spread to other cells. The team aims to further exploit CRISPR-Translate to uncover additional, yet uncharacterized, factors in the cellular antiviral defense mechanism.

“Detecting double-stranded RNA (dsRNA) is a key antiviral defense mechanism, as dsRNA is typically produced during viral infections and triggers various innate immune responses,” said corresponding author Rémi Buisson, PhD, UC Irvine associate professor of biological chemistry in the School of Medicine. “Understanding how cells recognize viral genomes and activate the signaling cascades that initiate antiviral defenses is crucial for developing next-generation antiviral therapies.”

In this study, Sunwoo Oh, a graduate student in Dr. Buisson’s lab, reveals that IRF2 is essential for expressing OAS3, an enzyme that detects viral genomes and activates the RNase L endonuclease to degrade viral RNA in infected cells. IRF2, critical for maintaining proper OAS3 expression, ensures the rapid activation of RNase L upon viral entry, blocking replication and preventing further virus propagation in the body.

“Identifying regulators of the host's innate immune response to prevent viral replication remains a critical research priority,” said Buisson. “This study illuminates how cells rapidly activate specific pathways of innate immune response within a few hours after infection.”

The other UC Irvine School of Medicine team members are Gisselle Santiago, Lavanya Manjunath and Junyi Li from the Department of Biological Chemistry, as well as Bert Semler, PhD, and graduate student Alexis Bouin from the Department of Microbiology and Molecular Genetics.

This work was supported by the National Institutes of Health (R37- CA252081) and a Research Scholar Grant from American Cancer Society (RSF-24-1249960-01-DMC).

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