Citation: Erlin Wang, Xinwei Huang, Yunshuang Ye, Shiqing Zou, Guijun Chen, Liping Yang, Nigel W. Fraser, Fukai Bao, Jumin Zhou, Xia Cao. Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I .VIROLOGICA SINICA, 2023, 38(1) : 108-118.  http://dx.doi.org/10.1016/j.virs.2022.11.008

Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I

  • Herpes simplex virus-1 (HSV-1) is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis (HSE) with a high mortality rate. Most patients present with changes in neurological and behavioral status, and survivors suffer long-term neurological sequelae. To date, the pathogenesis leading to brain damage is still not well understood. HSV-1 induced encephalitis in the central nervous system (CNS) in animals are usually very diffuse and progressing rapidly, and mostly fatal, making the analysis difficult. Here, we established a mouse model of HSE via intracerebral inoculation of modified version of neural-attenuated strains of HSV-1 (deletion of ICP34.5 and inserting a strong promoter into the latency-associated transcript region), in which the LMR-αΔpA strain initiated moderate productive infection, leading to strong host immune and inflammatory response characterized by persistent microglia activation. This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage, amyloidosis, Alzheimer's disease, and neurodegeneration, eventually leading to neuronal loss and behavioral changes characterized by hypokinesia. Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled, mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.

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    Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I

      Corresponding author: Jumin Zhou, zhoujm@mail.kiz.ac.cn
      Corresponding author: Xia Cao, caoxia@kmmu.edu.cn
    • a. Key Laboratory of Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, China;
    • b. Key Laboratory of Animal Models and Human Disease Mechanism of the Chinese Academy of Science/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, 650223, China;
    • c. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China;
    • d. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;
    • e. Department of Biology and Immunology, Kunming Medical University, Kunming, 650101, China;
    • f. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China

    Abstract: Herpes simplex virus-1 (HSV-1) is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis (HSE) with a high mortality rate. Most patients present with changes in neurological and behavioral status, and survivors suffer long-term neurological sequelae. To date, the pathogenesis leading to brain damage is still not well understood. HSV-1 induced encephalitis in the central nervous system (CNS) in animals are usually very diffuse and progressing rapidly, and mostly fatal, making the analysis difficult. Here, we established a mouse model of HSE via intracerebral inoculation of modified version of neural-attenuated strains of HSV-1 (deletion of ICP34.5 and inserting a strong promoter into the latency-associated transcript region), in which the LMR-αΔpA strain initiated moderate productive infection, leading to strong host immune and inflammatory response characterized by persistent microglia activation. This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage, amyloidosis, Alzheimer's disease, and neurodegeneration, eventually leading to neuronal loss and behavioral changes characterized by hypokinesia. Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled, mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.

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