Honokiol is a pleiotropic natural compound isolated from Magnolia and has multiple biological and clinically relevant effects,including anticancer and antimicrobial function.However,the antiviral activity of honokiol ...Honokiol is a pleiotropic natural compound isolated from Magnolia and has multiple biological and clinically relevant effects,including anticancer and antimicrobial function.However,the antiviral activity of honokiol has not yet been well studied.Here we showed that honokiol had no effect on herpes simplex virus-1(HSV-1)entry,but inhibited HSV-1 viral DNA replication,gene expression and the production of new progeny viruses.The combination of honokiol and clinical drug acyclovir augmented inhibition of HSV-1 infection.Our results illustrate that honokiol could be a potential new candidate for clinical consideration in the treatment of HSV-1 infection alone or combination with other therapeutics.展开更多
To date, 29 distinct microRNAs(miRNAs) have been reported to be expressed during herpes simplex virus infections.Sequence analysis of mature herpes simplex virus-1(HSV-1) miRNAs revealed five sets of miRNAs that are c...To date, 29 distinct microRNAs(miRNAs) have been reported to be expressed during herpes simplex virus infections.Sequence analysis of mature herpes simplex virus-1(HSV-1) miRNAs revealed five sets of miRNAs that are complementary to each other: miR-H6-5p/H1-3p, miR-H6-3p/H1-5p, H2-5p/H14-3p, miR-H2-3p/H14-5p, and miR-H7/H27.However, the roles of individual miRNAs and consequences of this complementarity remain unclear. Here, we focus on two of these complementary miRNAs, miR-H6-5p and miR-H1-3p, using loss-of-function experiments in vitro and in a mouse model of infection using an miRNA sponge approach, including tandem multiplex artificial miRNA-binding sequences that do not match perfectly to the target miRNA inserted downstream of a green fluorescent protein reporter gene. Infection with recombinant virus expressing the miR-H6-5p sponge reduced viral protein levels and virus yield.Decreased accumulation of viral proteins was also observed at early stages of infection in the presence of both an miR-H6-5p inhibitor and plasmid-expressed miR-H1-3p. Moreover, establishment of latency and reactivation did not differ between the recombinant virus expressing the miR-H6-5p sponge and wild-type HSV-1. Taken together, these data suggest that miR-H6-5p has an as-yet-unidentified role in the early stages of viral infection, and its complement miR-H1-3p suppresses this role in later stages of infection. This report extends understanding of the roles of miRNAs in infection by herpes simplex viruses, supporting a model of infection in which the production of virus and its virulent effects are tightly controlled to maximize persistence in the host and population.展开更多
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 the grant from National Key Research and Development Program (2016YFA0502100)
文摘Honokiol is a pleiotropic natural compound isolated from Magnolia and has multiple biological and clinically relevant effects,including anticancer and antimicrobial function.However,the antiviral activity of honokiol has not yet been well studied.Here we showed that honokiol had no effect on herpes simplex virus-1(HSV-1)entry,but inhibited HSV-1 viral DNA replication,gene expression and the production of new progeny viruses.The combination of honokiol and clinical drug acyclovir augmented inhibition of HSV-1 infection.Our results illustrate that honokiol could be a potential new candidate for clinical consideration in the treatment of HSV-1 infection alone or combination with other therapeutics.
基金supported by grants from Shenzhen Science and Innovation Commission Project Grants JCYJ20170411094933148Dapeng Research Project Grants KY20160301 to Shenzhen International Institute for Biomedical Research+1 种基金Guangzhou Science and Innovation Commission Project Grants 2016070100039Guangzhou Education Bureau Project Grants 1201620034 to Guangzhou Medical University
文摘To date, 29 distinct microRNAs(miRNAs) have been reported to be expressed during herpes simplex virus infections.Sequence analysis of mature herpes simplex virus-1(HSV-1) miRNAs revealed five sets of miRNAs that are complementary to each other: miR-H6-5p/H1-3p, miR-H6-3p/H1-5p, H2-5p/H14-3p, miR-H2-3p/H14-5p, and miR-H7/H27.However, the roles of individual miRNAs and consequences of this complementarity remain unclear. Here, we focus on two of these complementary miRNAs, miR-H6-5p and miR-H1-3p, using loss-of-function experiments in vitro and in a mouse model of infection using an miRNA sponge approach, including tandem multiplex artificial miRNA-binding sequences that do not match perfectly to the target miRNA inserted downstream of a green fluorescent protein reporter gene. Infection with recombinant virus expressing the miR-H6-5p sponge reduced viral protein levels and virus yield.Decreased accumulation of viral proteins was also observed at early stages of infection in the presence of both an miR-H6-5p inhibitor and plasmid-expressed miR-H1-3p. Moreover, establishment of latency and reactivation did not differ between the recombinant virus expressing the miR-H6-5p sponge and wild-type HSV-1. Taken together, these data suggest that miR-H6-5p has an as-yet-unidentified role in the early stages of viral infection, and its complement miR-H1-3p suppresses this role in later stages of infection. This report extends understanding of the roles of miRNAs in infection by herpes simplex viruses, supporting a model of infection in which the production of virus and its virulent effects are tightly controlled to maximize persistence in the host and population.
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.
