Catching viruses in the act of sabotage
Viruses are masters of sabotage, they can disable the cell’s antiviral defences and silence immune sensing systems—but this strategy can backfire. A collaborative study carried out by researchers at the University of California, Berkeley and the lab of Moritz Gaidt at the IMP uncovered how human immune cells can sense when viruses sabotage key cellular safeguards. They show that this hidden “backup alarm” triggers inflammation when viruses disable the cell’s defences. Their findings are published in the journal Science.
Once inside a cell, viruses deploy specialised proteins, known as effectors, to block antiviral defences and evade detection. This creates a major challenge for host cells: detecting invaders that actively try to stay hidden by disabling immune responses. While the human innate immune system is best known for recognising tell-tale molecular signatures found in viruses and bacteria, plants can also sense infection by detecting pathogen effectors—or the immune suppression they trigger. Whether a similar mechanism exists in humans has long remained unclear.
For decades, research on human innate immunity has focused almost exclusively on receptors that recognise foreign molecules, such as viral RNA or bacterial cell wall components. Meanwhile, studies in plants showed that cells can also detect pathogens indirectly—by sensing the activities of virulence factors when they attack critical host functions, a concept known as effector-triggered immunity. In mammals, however, such pathways have been difficult to identify, partly because viruses often deploy multiple strategies at once, masking immune responses during infection.
In a collaborative study between the laboratories of Russell Vance at the University of California, Berkeley and Moritz Gaidt at the IMP, researchers discovered a new way human immune cells detect viruses. Rather than recognising viral molecules, immune cells can detect when viruses sabotage key antiviral systems inside the cell. This interference is detected by the cell, which responds by triggering inflammation. The findings uncover a previously unknown layer of immune defence in humans and provide a roadmap for discovering additional pathways of this kind.
A new immune sensing mechanism in human cells
Viruses often evade the immune system by switching off the very signals that would normally reveal their presence. To understand how human immune cells might still detect such hidden infections, the researchers tested viral proteins one at a time. They expressed more than 100 proteins from myxoma virus—a poxvirus lethal to rabbits but harmless to humans—in human immune cells and monitored how the cells responded. This strategy allowed the scientists to isolate the effects of single viral proteins without interference from other viral factors that might normally suppress immune responses.
Out of all tested proteins, only one—called M3.1—triggered a strong inflammatory reaction. Further experiments revealed that this viral protein disables two of the cell’s core antiviral sensing and defence mechanisms—systems that normally prevent viruses from replicating inside cells. “That was surprising,” says Moritz Gaidt. “Disabling antiviral sensors and defences usually allows a virus to replicate undetected. But in this case, shutting down these pathways generates a secondary alarm signal.”
The researchers show that this response is caused by a built-in safety mechanism within the cell: the defences targeted by the virus also help keep immune responses under control. When the virus interferes with them, it inadvertently removes this restraint, switching inflammation on.
“The virus is trapped in a dilemma,” says Moritz Gaidt. “Either it leaves the cell’s defences intact and gets blocked—or it disables them and triggers an immune alarm.” The researchers describe this mechanism as a form of “self-guarding,” in which antiviral defences effectively protect themselves: if they are tampered with or inhibited, their disruption becomes the trigger for immune activation.
The findings show that human cells can sense infection not only by detecting viral molecules, but also by detecting viral sabotage. This shows that human cells can detect infection even when viruses successfully disable classical immune sensors. This reveals a new layer of the ongoing arms race between viruses and their hosts. Importantly, the work also provides a framework to uncover additional effector-triggered immune pathways in mammals. “Examples of this type of immune mechanism in human cells are still rare,” says Gaidt. “But we suspect there are more—and now we have a strategy to find them.”
Original Publication
B. C. Remick, J. Q. Mao, A. G. Manford, A. D. Gutierrez-Jensen, A. Wagner, M. Rape, G. McFadden, M. M. Rahman, M. M. Gaidt & R. E. Vance “Poxvirus attack of antiviral defense pathways unleashes an effector-triggered NF-κB response.” Science (2026). DOI: 10.1126/science.adw4937