The immune system’s ability to distinguish self from non-self is central to defending against infection. For years, the prevailing scientific belief was that the immune system responds to something viruses produce. In a groundbreaking study published in Nature, however, Siddharth Balachandran, PhD, Director of the Center for Immunology at Fox Chase, and his team of international collaborators have shown that, in fact, infected cells generate their own signals to trigger cell death and contain infection. These findings reveal a mechanism that has significant therapeutic potential for harnessing cell death pathways to fight not only infectious diseases, but also cancer.
In the Nature study, Balachandran and an international team of collaborators discovered that during herpes simplex virus and influenza infections, the immune sensor ZBP1 (Z-form nucleic acid-binding protein 1) is primarily activated not by viral RNAs, but by the host cell’s own “malformed” RNAs.
“The immune system has conventionally been thought to distinguish self from non-self during infections, meaning that what your immune system recognizes when you are infected is something that the virus or bacterium produces. But we have found that’s not the case during influenza and herpes virus infections. What our cells actually recognize to signal the presence of the virus is an alarm the cell has itself set off. And that’s novel,” said Balachandran.
This finding emerged from rigorous molecular investigations tracking exactly which RNA molecules bind to and activate ZBP1. The team discovered that the majority of RNAs bound to ZBP1 in infected cells were derived from the host cell, mapping to abnormally extended cellular transcripts rather than viral genomes.
The key to this discovery lies in the way viruses sabotage normal cellular processes. Both herpes simplex virus and influenza virus encode proteins (ICP27 and NS1, respectively) that deliberately disrupt the host cell’s transcription termination machinery. These proteins target a complex called CPSF, which normally ensures proper RNA processing.
When CPSF is disabled, cellular genes fail to terminate transcription properly, creating aberrantly long RNA transcripts. These extended regions often contain repetitive genomic elements in inverted orientations. When transcribed, these inverted repeats fold back on themselves, forming unusual left-handed double-helical structures called Z-RNAs.
ZBP1 specifically recognizes these Z-form RNAs. Upon binding host cell Z-RNAs, ZBP1 initiates programmed cell death pathways including necroptosis and apoptosis, effectively eliminating the infected cell before viral replication can proceed.
Balachandran’s team provided multiple lines of evidence that host Z-RNAs are sufficient to activate ZBP1:
Notably, viruses lacking ICP27 or NS1 failed to generate host Z-RNAs and showed significantly reduced ability to trigger ZBP1-mediated cell death, confirming that viral disruption of transcription termination is the critical upstream event.
These discoveries open multiple therapeutic avenues. The fact that ZBP1 responds to cellular stress signals rather than viral molecules directly suggests that activating this pathway could eliminate not only virus-infected cells but also cancer cells experiencing 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,” said Balachandran. “Normally this would involve using actual viruses, but there are all sorts of issues with storing, transporting, and deploying viruses. That’s where our research comes in.”
Balachandran and his team’s findings suggest that small molecules designed to induce Z-RNA formation in host cells could serve as immunogenic adjuvants for cancer immunotherapy. Balachandran’s lab is currently working with the Molecular Modeling Facility at Fox Chase to design a new class of small molecules that safely trigger these antiviral pathways in tumors and tumor microenvironment cells. They are investigating analogs of the compound JTE 607, an existing inhibitor of transcription termination, with the goal of overcoming its current pharmacological liabilities for effective cancer treatment.
The work of Dr. Balachandran and his colleagues exemplifies the caliber of science conducted at Fox Chase Cancer Center, one of only 57 NCI-designated Comprehensive Cancer Centers in the United States. Their discovery required sophisticated molecular biology; advanced sequencing technologies; computational biology; structural analysis; and collaborative expertise spanning immunology, virology, and cancer biology as well as collaboration from institutions around the globe—reflecting Fox Chase’s position as a hub for innovative biomedical research that translates basic science discoveries into better patient care.
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