Protecting ourselves from herpes: when trash becomes treasure
Mutations in a key gene that was thought to be 'junk' DNA are linked to the risk of encephalitis after HSV-1 infection.
November 21, 2022
Infections with Herpes simplex virus 1 (HSV-1) are very common and usually cause only minor symptoms. In rare cases, the HSV-1 infection goes awry and turns into herpes simplex encephalitis, a devastating brain disease that is lethal if left untreated. In a large, collaborative effort, researchers from the VIB-UGent Center for Inflammation Research, Ghent University, Ghent University Hospital, and the Cleveland Clinic Florida Research and Innovation Center identify mutations in a key gene that predisposes to encephalitis after HSV-1 infection. Their work appeared in Science Immunology.
In short:
- Billions of people are infected with Herpes simplex virus 1 (HSV-1).
- Usually, an HSV-1 infection proceeds asymptomatic, but in 1 in 250,000 – per year, this infection leads to potentially lethal brain inflammation (encephalitis).
- Mutations in the gene GTF3A predispose to encephalitis following HSV-1 infection by altered expression of a pseudogene, originally considered ‘junk’ DNA.
- The impaired expression of the pseudogene results in the spreading of HSV-1 to the brain.
- This is the first reported human disease related to GTF3A gene mutations.
A common virus
Around two-thirds of people worldwide are infected by HSV-1. It is one – if not the – most common infection in humans. In most cases, HSV-1 infection causes little to no symptoms. Most people will remain happily unaware of their infection. Occasionally, someone might develop blisters or ulcers at the site of infection.
However, in rare cases (1 in 250,000 – per year), HSV-1 infection leads to herpes simplex encephalitis – a devastating brain disease that is lethal if left untreated. Previous research discovered inborn errors in certain aspects of the immune system that increase the odds of developing encephalitis following HSV-1 infection, but not all the genetic details of these errors are known.
Dr. Simon Tavernier (VIB-UGent Center for Inflammation research): "Today, genetic screening of patients with a primary immunodeficiency focuses on known drivers of the disease. A causative error is identified in only 30% of the patients. In the PID Grand Challenges project, we aimed to identify new drivers of innate immune disorders through more extensive genetic research."
Turning deadly
By examining the immune system and DNA of a young Belgian patient with herpes simplex encephalitis (HSE), the teams of Prof. Rudi Beyaert and Prof. Jonathan Maelfait (all VIB-UGent Center for Inflammation Research), together with Prof. Dr. Filomeen Haerynck at Ghent University and Ghent University Hospital identified specific mutations associated with herpes-induced encephalitis.
Examining the whole genome, the researchers found mutations in the gene GTF3A. This gene codes for transcription factor IIIA (TFIIIA), a molecule that is involved in regulating DNA transcription. In other words, TFIIIA helps to express other genes. In people with the GTF3A mutations, however, TFIIIA is less active and seemingly increases the chance of herpes simplex encephalitis. How GTF3A protects us from herpes was not yet clear, until now.
Protection from an unexpected source
Together with the team of Dr. Michaela Gack in the Cleveland Clinic Florida Research and Innovation Center, the researchers identified a pseudogene, once considered ‘junk’ DNA, as the unexpected clue that solved the puzzle. During herpes infections in healthy individuals, TFIIIA activates the pseudogene. This pseudogene acts as a warning signal and alerts the immune system to the presence of herpes. When GTF3A is mutated, the pseudogene is not activated and the immune system fails to protect us from herpes.
Dr. Leslie Naesens (VIB-UGent Center for Inflammation Research): "Our discoveries show us a completely new way in which our immune system can protect us from viruses such as herpes. Rather than detecting the virus itself, our immune system looks for other kinds of danger signals, which apparently can even come from within. It’s one of these findings that learns us how ingeniously our immunity detects viruses that are constantly trying to deceive our immune system."
"This study sheds light on the cell-intrinsic immune response after herpes simplex infection. It helps us to better understand why certain people are selectively vulnerable to herpes simplex encephalitis and resistant to other invasive viral infections. These findings offer many families the possibility of molecular diagnosis and genetic counseling, preventing 16 000 - 32 000 HSE cases each year," says Prof. Dr. Filomeen Haerynck, who leads the PID research lab at Ghent University.
PID and VIB's Grand Challenges
This discovery resulted from the PID project that is part of VIB's Grand Challenges Program. PID stands for primary immune deficiencies. With the project, a consortium of researchers and clinicians addresses the need for a better understanding of different forms of PID and improved molecular diagnostic tools to stratify PID patients and guide therapeutic decisions in the clinic.
Publication
GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141. Naesens, Muppala, et al. Science Immunology, 2022.
Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: [email protected]. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.
