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Viruses are masters at taking over our cells: They disable our defenses and hijack the cellular machinery in order to multiply successfully. For example, the herpes simplex virus 1, which causes blister-like skin rashes, and influenza viruses specifically block a crucial step in gene activity in which the production of RNA molecules is completed鈥攌nown as transcription termination. The blockade results in unnaturally long RNA molecules that cannot be translated into proteins. This suppresses the antiviral defense in the cells and creates optimal conditions for the viruses to multiply.

A new study in Nature now shows that human cells are not helpless against this viral sabotage. They recognize the disruption of transcription termination as an alarm signal, activate a "self-destruction program" and sacrifice themselves鈥攅ven before the virus can multiply in them. This enables them to nip the spread of the infection in the bud.

Evolution has turned viral sabotage into defense

The international research team, from Philadelphia (U.S.), Charlestown (U.S.), Chengdu (China) and Hanover (Germany), discovered that the unnaturally long RNA molecules adopt a special structure: They twist into left-turning double strands, known as Z-RNAs. These unusual RNA forms are recognized by the cellular protein ZBP1. And then the controlled cell death begins.

It is particularly noteworthy that Z-RNAs form primarily in those sections of these unnaturally long RNA molecules that originate, among other things, from remnants of previous viral infections. These otherwise silent areas of our genome are only transcribed into RNA due to the virus-related disruption of transcription termination.

"Our cells therefore use these genetic remnants of ancient viral infections to detect and ward off current viral attacks," explains Prof. Lars D枚lken, one of the four corresponding authors of the paper. He heads the Institute of Virology at Hannover Medical School (MHH) and is the designated co-spokesperson of the Cluster of Excellence RESIST.

Evolution has thus turned the tables: what once began as a viral invasion now serves as an alarm signal for the antiviral immune defense. This discovery impressively demonstrates how closely virus and host have been intertwined over millions of years鈥攁nd how our cells can transform viral sabotage into highly effective protective strategies.

New perspectives for therapies

The discovery has far-reaching significance beyond viral infections. Unnaturally long RNA molecules resulting from disrupted transcription termination are also known to be involved in cellular stress reactions and cancer. This discovery could therefore inspire new therapeutic strategies.

In the future, drugs that specifically generate Z-RNAs or alter their recognition could be used to strengthen the immune system, treat autoimmune diseases, improve vaccines or optimize cancer immunotherapies鈥攆or example by stimulating tumor cells to self-destruct.