CRISPR Discovery Paves Way for Single Diagnostic Test for COVID, Flu and RSV

Immune systems across all forms of life defend against viruses by blocking their ability to replicate. Many CRISPR-based defenses achieve this by cutting viral DNA, but these approaches can damage host cells and limit therapeutic or diagnostic use. The challenge has been to stop viral replication precisely without harming healthy genetic material. New research now describes a CRISPR mechanism that halts virus protein production by targeting RNA, offering a safer and more controllable strategy that could support rapid diagnostics for respiratory infections.

In the collaborative research led by Utah State University (Logan, UT, USA), investigators studied lesser-known CRISPR systems Cas12a2 and Cas12a3. Unlike CRISPR-Cas9, which uses guide RNA to cut DNA at specific sites, Cas12a2 and Cas12a3 directly recognize RNA. Binding to viral RNA triggers a structural change in these enzymes, activating repeated cleavage of secondary targets. Cas12a3 stands out because it selectively targets transfer RNA rather than DNA, preserving host genetic material.

Image: USU chemists Kadin Crosby, Bamidele Filani, and Ryan Jackson have reported newly discovered functions of CRISPR-Cas12a3 (Photo courtesy of USU/M. Muffoletto)

Cas12a3 disrupts protein synthesis by cutting a specific region of transfer RNA known as the tail, which normally carries amino acids required to build proteins. By disabling this molecular bridge, the system prevents viruses from producing essential proteins while leaving host DNA intact. This precision contrasts with Cas12a2, which indiscriminately cleaves DNA after activation and ultimately kills the host cell. The selective RNA-based activity of Cas12a3 makes it particularly attractive for diagnostic and therapeutic applications.

Using structural and functional analyses, the researchers uncovered Cas12a3’s previously unknown immune response mechanism. The study showed that RNA recognition alone is sufficient to activate the enzyme and trigger targeted tRNA cleavage, effectively stopping viral replication. These findings, reported in the journal Nature, reveal a fundamentally different CRISPR defense strategy than those commonly used in gene editing or diagnostics today.

Because Cas12a3 responds to specific RNA sequences, it could be adapted into highly accurate diagnostic tools capable of detecting viral infections such as COVID-19, influenza, and RSV, either individually or together in a single test. Its repeated activation mechanism may amplify detection signals, enabling faster and more sensitive assays. Ongoing research aims to refine this system so it can be reliably harnessed for rapid point-of-care diagnostics and, potentially, future antiviral therapies.

“We think being able to stop an invading pathogen while leaving DNA unchanged could be a therapeutic breakthrough,” said Associate Professor Ryan Jackson, senior author of the study. “As we study these systems, we’re also discovering the enormous functional diversity in these bacterial defense mechanisms.”

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