Scientists use minibrains to study herpes encephalitis

Herpes simplex virus 1 can cause dangerous brain infections. Combining anti-inflammatory and antiviral drugs may help in such cases, scientists from the Rajewsky and Landthaler laboratories and the Organoid Platform at the Max Delbrück Center for Natural Microbiology report. ing.

About 3.7 billion people, or 67% of us, carry herpes simplex virus type 1 in our nerve cells, and the virus remains dormant until triggered by stress or injury. Once activated, symptoms are usually mild and limited to cold sores and mouth ulcers.

Very rarely, viruses can travel through neurons to reach the brain and cause life-threatening infections. It accounts for 5-15% of all cases of infectious encephalitis in children and adults. Doctors usually prescribe an antiviral drug called acyclovir. However, patients still often suffer from long-term, debilitating memory loss, seizures, and other cognitive deficits.

In such cases, doctors may try a combination of antivirals and anti-inflammatory drugs to see if that improves prognosis, according to scientists at the Helmholtz Society’s Max Delbrück Center for Molecular Medicine, in a new study. “Nature Microbiology” studies suggest. in Berlin. Scientists made this discovery using a three-dimensional model of the brain grown from human stem cells. The use of such models, called organoids, is at the forefront of clinical medicine.

“These primitive brains contain hundreds of thousands of neurons that can communicate with each other in synchrony. We can do important experiments with them that were impossible a few years ago.” Professor Nikolaus Radzewski, Scientific Director of the Berlin Institute, said: Senior author of Medical Systems Biology and Research at the Max Delbruck Center (MDC-BIMSB).

Dr. Agnieszka Rybak Wolf, head of the Organoid Technology Platform at the Max Delbrück Center and one of the first authors, created organoids, which are white 0.5 cm chunks. “Brain organoids are like tiny clouds of tissue,” she says.

Getting closer to the reality of herpes

Without organoids, analysis of HSV-1-induced encephalitis is difficult. The virus only infects humans, so taking these brain samples is impractical. Scientists have defaulted to studying the disease in cultured neurons or in mice that are not natural carriers of the virus.

“This model is much closer to the reality of the herpes virus than models that have been used before,” said a viral expert who studies the molecular mechanisms of HSV-1 infection in the Landthaler lab. Dr. Emmanuel Weiler, one of the lead authors, said: .

The researchers infected the organoids with the HSV-1 virus and visualized neuroepithelial and neuronal cells as the virus rampaged and collapsed the mini-brain. “We got a beautiful microscopic image that was very sharp and really showed what was going on,” says Wyler.

They then performed single-cell analysis to identify all molecular pathways active during infection. “We used an unbiased approach to discover all the important pathways and genes,” says Dr. Ivano Lenini, one of the first authors and a systems biologist formerly in the Lajowski lab. said. “We’re bringing systems biology to the table.”

They found that a signaling pathway important in inflammation called TNF-α was highly activated. Treatment of the organoids with acyclovir, a standard treatment for HSV-1 encephalitis, stopped viral replication but continued tissue damage. Further analysis showed that the TNF-α pathway remained active despite treatment.

Defense that can do damage

“The inflammatory pathway is an important natural defense against viruses,” says Tancredi Massimo Pentimari, Ph.D., Ph.D. in systems medicine, currently in the Rajusky lab, and one of the first authors. “However, blocking viral replication with antiviral drugs can result in an excessive inflammatory response that can be detrimental.”

Dr. Ryback Wolfe treated the organoids with both antiviral and anti-inflammatory drugs that block the TNF-α pathway. This combined treatment prevented damage to the minibrain. “There are signaling pathways in the brain that are activated during infection,” she says. “The organoids were not damaged when switched off with these agents.”

Researchers hope doctors will test acyclovir and anti-inflammatory drugs as a treatment for HSV-1 encephalitis. “Clinical investigators set up a clinical trial to evaluate the efficacy of new antiviral and anti-inflammatory drug combinations in patients with herpes encephalitis, ultimately translating our findings from the clinical setting to the bedside.” I hope so,” said Pentimali.

Max Delbruck Center

The Helmholtz Institute’s Max Delbrück Center for Molecular Medicine (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück from Berlin was a Nobel Prize winner and one of the founders of molecular biology. At his Buch and Mitte base in Berlin, researchers in some 70 countries study human biology, the foundations of life from its most basic building blocks to the mechanisms of entire systems. By understanding what controls or disrupts the dynamic balance of cells, organs, or the entire body, we can prevent disease, diagnose it early, and halt its progression with targeted therapies. Patients need to benefit from basic research discoveries as soon as possible. The Max Delbruck Center therefore supports the creation of spin-offs and participates in collaborative networks. It works in close collaboration with the jointly run Experimental and Clinical Research Center (ECRC), the Berlin Institute for Health Research (BIH) in Charité and the Charité University of the German Cardiovascular Research Center (DZHK). Founded in 1992, the Max Delbrück Center currently employs 1,800 people and is funded 90 percent by the German Federal Government and 10 percent by the State of Berlin.