Studying herpes encephalitis with mini-brains


The herpes simplex virus-1 can sometimes cause a dangerous brain infection. Combining an anti-inflammatory and an antiviral could help in these cases, report scientists with the Rajewsky and Landthaler labs and the Organoid Platform at the Max Delbrück Center in “Nature Microbiology."
About 3.7 billion people — 67% of us — carry the herpes simplex virus-1 in our nerves cells where it lies quiescent until triggered by stress or injury. When activated, its symptoms are usually mild, limited to cold sores or ulcers in our mouth.
Very rarely, the virus can travel up the neurons to the brain, where it can cause a life-threatening infection. This accounts for 5 to 15% of all cases of infectious encephalitis in children and adults. Doctors typically prescribe an anti-viral called acyclovir. But even so, the patients often suffer from long-lasting and debilitating memory loss, seizures and other cognitive disorders.
In such cases, doctors could trial an anti-viral in combination with a drug that curbs inflammation to see whether it offers a better prognosis, suggests a new “Nature Microbiology” study by scientists at the Max Delbrück Centre for Molecular Medicine in the Helmholtz Association in Berlin. The 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 frontier of clinical medicine.
“These proto-brains contain hundreds of thousands of neurons that can communicate with each other in a synchronized manner. Important experiments can be conducted with them that were impossible a few years ago,” says Professor Nikolaus Rajewsky, Scientific Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB) and senior author of the study.
Dr. Agnieszka Rybak-Wolf, who heads the Organoid Technology Platform at the Max Delbrück Center and is one of the first authors, created the organoids, which were white, 0.5 cm blobs. “Brain organoids look a bit like small clouds of tissue,” she says.  

Closer to reality for herpes

Without organoids, analyzing HSV-1-induced encephalitis is challenging. The virus infects only people and getting these brain samples is impractical. Scientists defaulted to studying the disease in cultured nerve cells or in mice, which are not natural carriers of the virus.  

“This model is now much closer to reality for the herpes virus than what has been used previously,” says Dr. Emanuel Wyler, a virus expert who studies the molecular mechanisms of HSV-1 infections at the Landthaler lab and one of the first authors.

The image shows how the herpes virus (white) spreads into the organoid and destroys the integrity of the neuroepithelium lining the ventricle (nuclei in blue, green marker for the neuroepithelium).
© Dr. Agnieszka Rybak-Wolf, Max Delbrück Center

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