Scientists have discovered that infected cells can essentially sound their own internal alarm, triggering self-destruction before a virus has a chance to spread. The finding, published in Nature, reveals a previously unknown immune mechanism that could one day be harnessed to fight both infectious diseases and cancer.
The international team, led by Siddharth Balachandran, PhD, at Fox Chase Cancer Center, found that during infections with herpes simplex virus and influenza, the immune sensor ZBP1 is not primarily activated by the virus itself. Instead, it responds to the host cell’s own “malformed” RNA. “What our cells actually recognize to signal the presence of the virus is an alarm the cell has itself set off,” Balachandran said. “And that’s novel.”
The discovery centers on how viruses disrupt normal cellular machinery. Both herpes and influenza produce proteins that disable a complex called CPSF, which normally ensures proper RNA processing. When CPSF is blocked, cellular genes produce abnormally long RNA transcripts. Some of these extended regions contain inverted repeats that fold back on themselves, forming unusual left-handed double-helical structures known as Z-RNAs. ZBP1 recognizes these Z-RNAs and triggers programmed cell death pathways, including necroptosis and apoptosis. In effect, the infected cell destroys itself before the virus can replicate.
The team confirmed this mechanism through several lines of evidence. Viruses lacking the key disruptive proteins did not generate host Z-RNAs effectively and were much less able to trigger ZBP1-mediated cell death. This confirmed that viral disruption of transcription termination is the critical upstream event.
Because ZBP1 responds to cellular stress signals rather than directly to viral molecules, the findings open several therapeutic possibilities. Activating this pathway could potentially eliminate virus-infected cells and cancer cells under transcriptional stress. “Our immune systems are designed to fight viruses, so if we can mimic a viral infection within the tumor mass, we can turn our immune system against it,” Balachandran said.
Balachandran’s lab is now working to design a new class of small molecules that safely activate these antiviral pathways in tumors. The researchers are also studying analogs of JTE 607, an existing inhibitor of transcription termination, aiming to overcome its current pharmacological limitations. The goal is to move closer to an effective cancer treatment strategy that does not require actual viruses for delivery.
“Normally this would involve using actual viruses, but there are all sorts of issues with storing, transporting, and deploying viruses,” Balachandran noted. “That’s where our research comes in.” The work represents a promising step toward turning the body’s own internal alarm system into a weapon against disease.