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

Erlin Wang ¹Xinwei Huang ²Yunshuang Ye ³Shiqing Zou ⁴Guijun Chen ³Liping Yang ³Nigel W.Fraser ⁵Fukai Bao ⁶Jumin Zhou ⁷Xia Cao²

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作者信息

1. Key Laboratory of Second Affiliated Hospital of Kunming Medical University,Kunming 650000,China;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
2. Key Laboratory of Second Affiliated Hospital of Kunming Medical University,Kunming 650000,China
3. 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
4. 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;Kunming College of Life Science,University of Chinese Academy of Sciences,Kunming 650204,China
5. Department of Microbiology,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA,19104,USA
6. Department of Biology and Immunology,Kunming Medical University,Kunming,650101,China
7. 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;KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,Kunming,650223,China
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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 patho-genesis 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 char-acterized 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.

Key words

Herpes simplex virus-1(HSV-1)/Herpes simplex encephalitis(HSE)/ICP34.5/Neuroinflammation/Neuronal loss

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基金项目

National Natural Science Foundation of China-Yunnan Joint Found(NSFC)(U2202215)

National Natural Science Foundation of China-Yunnan Joint Found(NSFC)(U1602226)

National Natural Science Foundation of China(NSFC)(81672040)

National Natural Science Foundation of China(NSFC)(8206306)

National Natural Science Foundation of China(NSFC)(31802026)

Ministry of Science and Technology of China(MOST)(2018YFC2000402)

Ministry of Science and Technology of China(MOST)(2018YFE0203700)

Ministry of Science and Technology of China Foreign Expert Program(G2021061008L)

CAS"Light of West China"Program(xbzgzdsys-201909)

a Thousand Foreign Talent scholarship from Yunnan Province()

Highend Foreign Expert Project of Yunnan Revitalization Talent Support Program()

Technology Innovation Team of Kunming Medical University(CXTD201804)

International Science and Technology Cooperation Project(2017IB011)

Yunnan Training Project for Medical Talents(L-2017014)

biomedical Special Project of the Department of Science and Technology of Yunnan Province(202102AA100007-4)

Chinese Academy of Sciences President's International Fellowship Initiative(PIFI)(2019VBA0045)

China Postdoctoral Science Foundation(2022MD713758)

Medical reserve Talents Training Program of Yunnan Provincial Health Commission of China(H-2019059)

Yunnan Fundamental Research Projects(202201AT070195)

Open Research Fund(HXDT-2019-1)

出版年

2023

中国病毒学

中国科学院武汉病毒研究所，中国微生物学会

中国病毒学

CSTPCDCSCD北大核心

影响因子：0.393

ISSN：1674-0769

参考文献量53

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