MSGID: 1:317/3 64951fe3   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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   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   
      
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   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.   
      
      
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   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   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/06/230622120820.htm   
      
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