International study involving the MHH shows how a viral attack turns into a highly effective cellular defence
Prof. Dölken observes cells through a microscope in a laboratory at the Institute of Virology at Hannover Medical School. Copyright: Karin Kaiser/MHH
Viruses are masters at taking over our cells: They disable our defences 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 - known as transcription termination. The blockade results in unnaturally long RNA molecules that cannot be translated into proteins. This suppresses the antiviral defence in the cells and creates optimal conditions for the viruses to multiply.
A new study in the renowned scientific journal Nature now shows that human cells are not helpless against this viral sabotage. They recognise the disruption of transcription termination as an alarm signal, activate a "self-destruction programme" and sacrifice themselves – even before the virus can multiply in them. This enables them to nip the spread of the infection in the bud. These are the research findings of an international team from Philadelphia (USA), Charlestown (USA), Chengdu (China) and Hanover.
Evolution has turned viral sabotage into defence
The research team 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 recognised 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 Dölken, 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 defence. This discovery impressively demonstrates how closely virus and host have been intertwined over millions of years – and 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 optimise cancer immunotherapies – for example by stimulating tumour cells to self-destruct.
The research is being continued as part of the newly established DFG Research Training Group ACME (Activation of Cellular Anti-Microbial Effectors). Researchers are looking for new cellular defence mechanisms against viruses and bacteria and are training young scientists in the process. The project is being funded by the German Research Foundation for five years and will start in April 2026.
Text: Bettina Bandel