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 neuro...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 neuralattenuated 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.展开更多
基金supported by grants from the National Natural Science Foundation of China-Yunnan Joint Found(NSFC,U2202215,U1602226)the National Natural Science Foundation of China(NSFC,81672040 to J.Zhou,8206306 to X.Cao,and 31802026 to L.Li)+11 种基金the Ministry of Science and Technology of China(MOST,2018YFC2000402,2018YFE0203700)the Ministry of Science and Technology of China Foreign Expert Program to J.Zhou(G2021061008L)the CAS“Light of West China”Program(xbzg-zdsys-201909)to J.Zhou,a Thousand Foreign Talent scholarship from Yunnan Province and High-end Foreign Expert Project of Yunnan Revitalization Talent Support Program to J.Zhouthe Technology Innovation Team of Kunming Medical University(CXTD201804)the International Science and Technology Cooperation Project(2017IB011)the Yunnan Training Project for Medical Talents(L-2017014)the biomedical Special Project of the Department of Science and Technology of Yunnan Province(202102AA100007-4)to X.Caothe Chinese Academy of Sciences President's International Fellowship Initiative(PIFI,2019VBA0045)to N.W.Fraserthe China Postdoctoral Science Foundation(2022MD713758)to E.Wangthe Medical reserve Talents Training Program of Yunnan Provincial Health Commission of China(H-2019059)to X.Huangthe Yunnan Fundamental Research Projects(202201AT070195)to Y.Ye.Open Research Fund HXDT-2019-1 to J.Zhou.
文摘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 neuralattenuated 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.
