Eight different herpes viruses are known to date in humans. All these permanently settle in the body after acute infection. Under certain circumstances, they wake up from this dormant state, multiply and attack other cells. This reactivation is often associated with symptoms, such as itchy cold sores or shingles.
Over the course of evolution, most herpesviruses have learned to use small RNA molecules, so-called microRNAs, to reprogram their host cells to their advantage. A research team led by Bhupesh Prusti and Lars Dolken from the Julius-Maximilians-Universitat (JMU) Würzburg in Bavaria, Germany is now able to show for the first time that a viral microRNA acts as a master regulator to induce reactivation. Can go Virus. in the magazine NatureResearchers present a previously unknown cellular mechanism by which human herpesvirus 6 (HHV-6) triggers its own awakening.
Problems after virus reactivation
More than 90 percent of all people are infected with HHV-6 without ever noticing it. The virus probably only causes problems when it wakes up frequently.
Reactivation of HHV-6 is suspected to impair heart function, leading to rejection of transplanted organs and triggering diseases such as multiple sclerosis or chronic fatigue syndrome (ME/CFS). In addition, recent studies suggest that this herpesvirus may be involved in the development of schizophrenia, bipolar disorder, and other diseases of the nervous system.
“How herpesviruses reactivate from a dormant state is a central question in herpesvirus research,” says JMU virologist Lars Dolken. “If we understand this, we know how to intervene therapeutically.” A previously unknown key to this is a viral microRNA called miR-aU14. This is the central switch that initiates the reactivation of HHV-6.
What does microRNA do in the cell
The regulator miR-aU14 comes from the virus itself. As soon as it is expressed, it interferes with the metabolism of human microRNAs. In doing so, it selectively interferes with the maturation of several microRNAs of the miR-30 family. As a result, these important cellular microRNAs are no longer produced. This in turn affects a cellular signaling pathway, the so-called miR-30/p53/Drp1 axis.
Through this pathway, viral miR-aU14 induces mitochondrial fission. These cell structures are of central importance for energy production, but also for signal transmission in defense against viruses.
Thus the viral miR-aU14 interferes with the production of type I interferon – the messenger substance with which the cell signals the presence of the virus to the immune system. Because interferons are missing, the herpesvirus is able to switch from an inactive state to an active state unhindered. Interestingly, the Würzburg research group was also able to show that the viral microRNA is not only essential for virus replication, but also directly triggers reactivation from the virus’s dormant state.
how the research continues
The researchers now want to understand the precise mechanism by which the viral microRNA initiates the reactivation of the virus. Furthermore, there are first indications that other herpesviruses may also be reactivated through the same mechanism. This may reveal therapeutic options to inhibit the reactivation of these viruses or to specifically trigger it so as to eliminate the reactivating cells. Another goal is to understand in detail the molecular consequences of mitochondrial fission.
For the first time, this work by Würzberg shows that one microRNA can directly control the maturation process of other microRNAs. It also opens up new therapeutic possibilities: artificial small RNAs can be specifically designed to cleave individual members of microRNA families. Such subtle interventions were not possible until now.
Collaboration Partners and Sponsors
Several groups at JMU are conducting interdisciplinary research on this topic. They come from the Institute of Virology and Immunobiology, the Biocenter’s Chairs of Biochemistry, Biotechnology and Biophysics, and Microbiology, the Rudolf Virchow Center and the Helmholtz Institute for RNA-Based Infection Research. Researchers from the Open University of Berlin and the University of Regensburg were also involved.
The research was funded within the framework of the Helmholtz Institute for RNA-Based Infection Research, the Hull ME/CFS Initiative (USA), the HHV-6 Foundation (USA), the Immortal Foundation (USA) and the European Research Council. An ERC grant.