Studying herpes encephalitis with mini-brains

Date:
June 22, 2023
Source:
Max Delbru"ck Center for Molecular Medicine in the Helmholtz
Association
Summary:
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.


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FULL STORY ==========================================================================
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 Delbru"ck 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 Delbru"ck 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 Delbru"ck Center (MDC-BIMSB) and senior author of the study.

Dr. Agnieszka Rybak-Wolf, who heads the Organoid Technology Platform at
the Max Delbru"ck 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 scientists infected the organoids with the HSV-1 virus and visualized
the neuroepithelial and neuronal cells as the virus rampaged and the
mini-brain disintegrated. "We had these beautiful microscopy images that
are so clear and you can see what is actually going on," Wyler says.

They next conducted a single cell analysis to identify all the molecular pathways active during infection. "We used an unbiased approach to
find all the pathways and genes that matter," says Dr. Ivano Legnini,
a systems biologist previously at the Rajewsky lab, and one of the first authors. "We bring systems biology to the table." They noticed that a signaling pathway important in inflammation, called TNF-a, was highly
active. When they treated the organoids with acyclovir, the standard
of care for HSV-1 encephalitis, viral replication stopped -- but the
tissue damage continued. Further analysis showed the TNF-a pathway was
still active despite treatment.

A defense that can become damaging "The inflammation pathway is a key
natural defense to the virus," says Dr.

Tancredi Massimo Pentimalli, a medical doctor now doing his PhD in
systems medicine at the Rajewsky lab and one of the first authors. "But
when we block viral replication with anti-viral drugs, the overzealous inflammatory response could instead become damaging." Rybak-Wolf treated
the organoids with both an anti-viral and an anti- inflammatory drug,
which would turn off the TNF-a pathway. This combined treatment prevented
the damage of mini-brains. "There is a signaling pathway in the brain
that becomes active during infection," she says. "When we switched it off
using these drugs, the organoid wasn't damaged." The scientists hope
doctors will trial acyclovir and an anti-inflammatory as a treatment
for HSV-1 encephalitis. "I hope that clinical investigators will set
up clinical trials evaluating the efficacy of new anti-viral and anti- inflammatory combination therapies in herpes encephalitis patients,
ultimately translating our findings from the bench to the bed side,"
Pentimalli says.

* RELATED_TOPICS
o Health_&_Medicine
# Viruses # Herpes # Infectious_Diseases # Encephalitis
o Plants_&_Animals
# Virology # Mice # Microbiology # Molecular_Biology
* RELATED_TERMS
o Chickenpox o Epstein-Barr_virus o Antiviral_drug o
West_Nile_virus o Natural_killer_cell o Rheumatic_fever o
Gastroenteritis o Rabies

========================================================================== Story Source: Materials provided by Max_Delbru"ck_Center_for_Molecular_Medicine_in_the
Helmholtz_Association. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Agnieszka Rybak-Wolf, Emanuel Wyler, Tancredi Massimo Pentimalli,
Ivano
Legnini et al. Modeling herpes simplex virus 1 infection in
cerebral organoids reveals new potential therapeutic approaches
for viral encephalitis. Nature Microbiology, 2023 DOI:
10.1038/s41564-023-01405-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230622120820.htm

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