肠道病毒EV71感染致中枢神经系统损伤机制及治疗研究进展
摘要
<正>肠道病毒71型(enterovirus 71,EV71)具有高度的嗜神经性,是儿童手足口病(Hand-Foot-Mouth disease,HFMD)和疱疹性咽峡炎的主要病原体之一,感染严重者可引起中枢神经系统损伤和神经源性肺水肿(neurogenic pulmonary edema,NPE)等病变,甚至危及生命[1]。研究[2]表明,近年来EV71在亚太地区流行呈上升趋势,且在我国局部地区也发
引文
[1]Park SK,Park B,Ki M,et al.Transmission of seasonal outbreak of childhood enteroviral aseptic meningitis and handfoot-mouth disease[J].J Korean Med Sci,2010,25(5):677-683.
[2]de la Caridad M,Quintana F.EMERGENCY OF CVA6AND EV71CAUSING HAND,FOOT AND MOUTH DISEASE IN CUBA,2011-2013[C]//8th Cuban Congress on Microbiology and Parasitology,5th National Congress on Tropical Medicine and 5th International Symposium on HIV/aids infection in Cuba.2014.
[3]He Y,Ong KC,Gao Z,et al.Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis[J].Am J Pathol,2014,184(3):714-720.
[4]Schmidt NJ,Lennette EH,Ho HH.An apparently new enterovirus isolated from patients with disease of the central nervous system[J].J Infect Dis,1974,129(3):304-309.
[5]孙乐乐,温红玲,王志玉.肠道病毒71型致病机制研究进展[J].病毒学报,2015,31(2):192-196.
[6]Brown BA,Oberste MS,Alexander JP Jr,et al.Molecular epidemiology and evolution of enterovirus 71strains isolated from 1970to 1998[J].J Virol,1999,73(12):9969-9975.
[7]刘娟,李康,杨静,等.肠道病毒71型(EV71)ICR乳鼠动物模型的建立[J].军事医学,2011,35(11):862-866.
[8]Chang LY,Huang LM,Gau SS,et al.Neurodevelopment and cognition in children after enterovirus 71infection[J].N Engl J Med,2007,356(12):1226-1234.
[9]胡琼文,谢婷婷,马永平.EV71亚单位VP1的原核表达、纯化及免疫原性分析[J].现代预防医学,2014,41(24):4478-4481.
[10]陈庆会.肠道病毒71型致手足口病合并脑炎81例临床分析[J].中国感染控制杂志,2011,10(5):354-356.
[11]陈冉冉,何颜霞,曾洪武,等.肠道病毒71型手足口病合并脑干脑炎患儿的远期随访[J].中华实用儿科临床杂志,2015(19):1501-1504.
[12]Huang MC,Wang SM,Hsu YW,et al.Long-term cognitive and motor deficits after enterovirus 71brainstem encephalitis in children[J].Pediatrics,2006,118(6):1785-1788.
[13]Cheng H,Zeng J,Li H,et al.Neuroimaging of HFMD infected by EV71[J].Radiology of Infectious Diseases,2015,1(2):103-108.
[14]彭炳蔚,杜志宏,李小晶,等.从临床和磁共振成像看非脊髓灰质炎肠道病毒71型相关性急性弛缓性瘫痪的演变和预后[J].中华儿科杂志,2012,50(4):255-260.
[15]Liu K,Ma YX,Zhang CB,et al.Neurologic complications in children with enterovirus 71-infected hand-foot-mouth disease:clinical features,MRI findings and follow-up study[J].Zhonghua Yi Xue Za Zhi,2012,92(25):1742-1746.
[16]Gau SS,Chang LY,Huang LM,et al.Attention-deficit/hyperactivity-related symptoms among children with enterovirus 71infection of the central nervous system[J].Pediatrics,2008,122(2):452-458.
[17]Tsou YA,Cheng YK,Chung HK,et al.Upper aerodigestive tract sequelae in severe enterovirus 71infection:predictors and outcome[J].Int J Pediatr Otorhinolaryngol,2008,72(1):41-47.
[18]Lin YW,Chang KC,Kao CM,et al.Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads[J].J Virol,2009,83(13):6477-6483.
[19]李军,姜琴,孟红,等.肠道病毒71型感染后组织病理改变实验研究[J].中国实用儿科杂志,2013,28(7):540-542.
[20]Khong WX,Yan B,Yeo H,et al.A non-mouse-adapted enterovirus 71(EV71)strain exhibits neurotropism,causing neurological manifestations in a novel mouse model of EV71infection[J].J Virol,2012,86(4):2121-2131.
[21]郝博,高迪,汤大为,等.肠道病毒71型在脑干脑炎婴幼儿脑干中的分布及感染机制[J].法医学杂志,2012,28(2):85-88,91.
[22]Yip CC,Lau SK,Lo JY,et al.Genetic characterization of EV71isolates from 2004to 2010reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2in Hong Kong[J].Virol J,2013,10:222.
[23]Teng S,Wei Y,Zhao SY,et al.Intestinal detoxification time of hand-foot-and-mouth disease in children with EV71infection and the related factors[J].World J Pediatr,2015,11(4):380-385.
[24]Wong KT,Munisamy B,Ong KC,et al.The distribution of inflammation and virus in human enterovirus 71encephalomyelitis suggests possible viral spread by neural pathways[J].J Neuropathol Exp Neurol,2008,67(2):162-169.
[25]Chen CS,Yao YC,Lin SC,et al.Retrograde axonal transport:a major transmission route of enterovirus 71in mice[J].J Virol,2007,81(17):8996-9003.
[26]shih SR,Stollar V,Lin JY,etal.Identification of genes involved in the host response to enterovirus 71infection[J].J Neurovirol,2004,10(5):293-304.
[27]Ho HY,Cheng ML,Weng SF,et al.Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71infection[J].J Gen Virol,2008,89(9):2080-2089.
[28]Yamayoshi S,Yamashita Y,Li J,et al.Scavenger receptor B2is a cellular receptor for enterovirus 71[J].Nat Med,2009,15(7):798-801.
[29]Tan CW,Chan YF.Enterovirus 71receptors:promising drug targets[J].Expert Rev Anti Infect Ther,2013,11(6):547-549.
[30]Tan CW,Lai JK,Sam IC,et al.Recent developments in antiviral agents against enterovirus 71infection[J].J Biomed Sci,2014,21:14.
[31]秦咸蕴.以肠道病毒71型3C蛋白酶为靶点的药物筛选模型的建立及药物筛选[D].济南:曲阜师范大学,2011.
[32]王静.EV71 3C蛋白酶及其与抗病毒药物相互作用的结构生物学研究[D].北京:北京协和医学院,2011.
[33]Kuo CJ,Shie JJ,Fang JM,et al.Design,synthesis,and evaluation of 3C protease inhibitors as anti-enterovirus 71agents[J].Bioorg Med Chem,2008,16(15):7388-7398.
[34]Lin L,Qin Y,Wu H,et al.Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down-regulating ubiquitin-proteasome system[J].Virus Res,2015,195:207-216.
[35]Shang L,Wang Y,Qing J,et al.An adenosine nucleoside analogue NITD008inhibits EV71proliferation[J].Antiviral Res,2014,112:47-58.
[36]Hung HC,Chen TC,Fang MY,et al.Inhibition of enterovirus71 replication and the viral 3D polymerase by aurintricarboxylic acid[J].J Antimicrob Chemother,2010,65(4):676-683.
[37]Velu AB,Chen GW,Hsieh PT,et al.BPR-3P0128inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71[J].Antiviral Res,2014,112:18-25.
[38]Wang SM,Ho TS,Shen CF,et al.Enterovirus 71,one virus and many stories[J].Pediatr Neonatol,2008,49(4):113-115.
[39]Cao R,Han J,Deng Y,et al.Presence of high-titer neutralizing antibodies against enterovirus 71in intravenous immunoglobulin manufactured from Chinese donors[J].Clin Infect Dis,2010,50(1):125-126.
[40]Kiener TK,Jia Q,Meng T,et al.A novel universal neutralizing monoclonal antibody against enterovirus 71that targets the highly conserved“knob”region of VP3protein[J].PLoS Negl Trop Dis,2014,8(5):2895.
[41]Nagata N,Iwasaki T,Ami Y,et al.Differential localization of neurons susceptible to enterovirus 71and poliovirus type 1in the central nervous system of cynomolgus monkeys after intravenous inoculation[J].J Gen Virol,2004,85(10):2981-2989.
[42]McMinn PC.Recent advances in the molecular epidemiology and control of human enterovirus 71infection[J].Curr Opin Virol,2012,2(2):199-205.
[43]Mat-Rahim NA,Abubakar S.Human Enterovirus 71 DNA Vaccine Constructs Containing 5′UTR with Complete Internal Ribosome Entry Site Sequence Stimulated Improved Anti-Human Enterovirus 71Neutralizing Immune Responses[J].World Journal of Vaccines,2014,4(1):33-43.
[44]Wu CN,Lin YC,Fann C,et al.Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1vaccines and inactivated virus[J].Vaccine,2001,20(5-6):895-904.
[45]Zhu FC,Meng FY,Li JX,et al.Efficacy,safety,and immunology of an inactivated alum-adjuvant enterovirus 71vaccine in children in China:a multicentre,randomised,double-blind,placebo-controlled,phase 3trial[J].Lancet,2013,381(9882):2024-2032.
[46]Liu CC,Hwang CS,Yang WS,et al.Long-term immunogenicity studies of formalin-inactivated enterovirus 71whole-virion vaccine in macaques[J].PLoS ONE,2014,9(9):106756.
[47]Li R,Liu L,Mo Z,et al.An inactivated enterovirus 71vaccine in healthy children[J].N Engl J Med,2014,370(9):829-837.
[48]Roldo A,Mellado MC,Castilho LR,et al.Virus-like particles in vaccine development[J].Expert Rev Vaccines,2010,9(10):1149-1176.
[49]Chung CY,Chen CY,Lin SY,et al.Enterovirus 71virus-like particle vaccine:improved production conditions for enhanced yield[J].Vaccine,2010,28(43):6951-6957.
[50]Ku Z,Ye X,Huang X,et al.Neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71genotype C4inhibit infection at pre-and post-attachment steps[J].PLoS ONE,2013,8(2):57601.
[2]de la Caridad M,Quintana F.EMERGENCY OF CVA6AND EV71CAUSING HAND,FOOT AND MOUTH DISEASE IN CUBA,2011-2013[C]//8th Cuban Congress on Microbiology and Parasitology,5th National Congress on Tropical Medicine and 5th International Symposium on HIV/aids infection in Cuba.2014.
[3]He Y,Ong KC,Gao Z,et al.Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis[J].Am J Pathol,2014,184(3):714-720.
[4]Schmidt NJ,Lennette EH,Ho HH.An apparently new enterovirus isolated from patients with disease of the central nervous system[J].J Infect Dis,1974,129(3):304-309.
[5]孙乐乐,温红玲,王志玉.肠道病毒71型致病机制研究进展[J].病毒学报,2015,31(2):192-196.
[6]Brown BA,Oberste MS,Alexander JP Jr,et al.Molecular epidemiology and evolution of enterovirus 71strains isolated from 1970to 1998[J].J Virol,1999,73(12):9969-9975.
[7]刘娟,李康,杨静,等.肠道病毒71型(EV71)ICR乳鼠动物模型的建立[J].军事医学,2011,35(11):862-866.
[8]Chang LY,Huang LM,Gau SS,et al.Neurodevelopment and cognition in children after enterovirus 71infection[J].N Engl J Med,2007,356(12):1226-1234.
[9]胡琼文,谢婷婷,马永平.EV71亚单位VP1的原核表达、纯化及免疫原性分析[J].现代预防医学,2014,41(24):4478-4481.
[10]陈庆会.肠道病毒71型致手足口病合并脑炎81例临床分析[J].中国感染控制杂志,2011,10(5):354-356.
[11]陈冉冉,何颜霞,曾洪武,等.肠道病毒71型手足口病合并脑干脑炎患儿的远期随访[J].中华实用儿科临床杂志,2015(19):1501-1504.
[12]Huang MC,Wang SM,Hsu YW,et al.Long-term cognitive and motor deficits after enterovirus 71brainstem encephalitis in children[J].Pediatrics,2006,118(6):1785-1788.
[13]Cheng H,Zeng J,Li H,et al.Neuroimaging of HFMD infected by EV71[J].Radiology of Infectious Diseases,2015,1(2):103-108.
[14]彭炳蔚,杜志宏,李小晶,等.从临床和磁共振成像看非脊髓灰质炎肠道病毒71型相关性急性弛缓性瘫痪的演变和预后[J].中华儿科杂志,2012,50(4):255-260.
[15]Liu K,Ma YX,Zhang CB,et al.Neurologic complications in children with enterovirus 71-infected hand-foot-mouth disease:clinical features,MRI findings and follow-up study[J].Zhonghua Yi Xue Za Zhi,2012,92(25):1742-1746.
[16]Gau SS,Chang LY,Huang LM,et al.Attention-deficit/hyperactivity-related symptoms among children with enterovirus 71infection of the central nervous system[J].Pediatrics,2008,122(2):452-458.
[17]Tsou YA,Cheng YK,Chung HK,et al.Upper aerodigestive tract sequelae in severe enterovirus 71infection:predictors and outcome[J].Int J Pediatr Otorhinolaryngol,2008,72(1):41-47.
[18]Lin YW,Chang KC,Kao CM,et al.Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads[J].J Virol,2009,83(13):6477-6483.
[19]李军,姜琴,孟红,等.肠道病毒71型感染后组织病理改变实验研究[J].中国实用儿科杂志,2013,28(7):540-542.
[20]Khong WX,Yan B,Yeo H,et al.A non-mouse-adapted enterovirus 71(EV71)strain exhibits neurotropism,causing neurological manifestations in a novel mouse model of EV71infection[J].J Virol,2012,86(4):2121-2131.
[21]郝博,高迪,汤大为,等.肠道病毒71型在脑干脑炎婴幼儿脑干中的分布及感染机制[J].法医学杂志,2012,28(2):85-88,91.
[22]Yip CC,Lau SK,Lo JY,et al.Genetic characterization of EV71isolates from 2004to 2010reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2in Hong Kong[J].Virol J,2013,10:222.
[23]Teng S,Wei Y,Zhao SY,et al.Intestinal detoxification time of hand-foot-and-mouth disease in children with EV71infection and the related factors[J].World J Pediatr,2015,11(4):380-385.
[24]Wong KT,Munisamy B,Ong KC,et al.The distribution of inflammation and virus in human enterovirus 71encephalomyelitis suggests possible viral spread by neural pathways[J].J Neuropathol Exp Neurol,2008,67(2):162-169.
[25]Chen CS,Yao YC,Lin SC,et al.Retrograde axonal transport:a major transmission route of enterovirus 71in mice[J].J Virol,2007,81(17):8996-9003.
[26]shih SR,Stollar V,Lin JY,etal.Identification of genes involved in the host response to enterovirus 71infection[J].J Neurovirol,2004,10(5):293-304.
[27]Ho HY,Cheng ML,Weng SF,et al.Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71infection[J].J Gen Virol,2008,89(9):2080-2089.
[28]Yamayoshi S,Yamashita Y,Li J,et al.Scavenger receptor B2is a cellular receptor for enterovirus 71[J].Nat Med,2009,15(7):798-801.
[29]Tan CW,Chan YF.Enterovirus 71receptors:promising drug targets[J].Expert Rev Anti Infect Ther,2013,11(6):547-549.
[30]Tan CW,Lai JK,Sam IC,et al.Recent developments in antiviral agents against enterovirus 71infection[J].J Biomed Sci,2014,21:14.
[31]秦咸蕴.以肠道病毒71型3C蛋白酶为靶点的药物筛选模型的建立及药物筛选[D].济南:曲阜师范大学,2011.
[32]王静.EV71 3C蛋白酶及其与抗病毒药物相互作用的结构生物学研究[D].北京:北京协和医学院,2011.
[33]Kuo CJ,Shie JJ,Fang JM,et al.Design,synthesis,and evaluation of 3C protease inhibitors as anti-enterovirus 71agents[J].Bioorg Med Chem,2008,16(15):7388-7398.
[34]Lin L,Qin Y,Wu H,et al.Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down-regulating ubiquitin-proteasome system[J].Virus Res,2015,195:207-216.
[35]Shang L,Wang Y,Qing J,et al.An adenosine nucleoside analogue NITD008inhibits EV71proliferation[J].Antiviral Res,2014,112:47-58.
[36]Hung HC,Chen TC,Fang MY,et al.Inhibition of enterovirus71 replication and the viral 3D polymerase by aurintricarboxylic acid[J].J Antimicrob Chemother,2010,65(4):676-683.
[37]Velu AB,Chen GW,Hsieh PT,et al.BPR-3P0128inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71[J].Antiviral Res,2014,112:18-25.
[38]Wang SM,Ho TS,Shen CF,et al.Enterovirus 71,one virus and many stories[J].Pediatr Neonatol,2008,49(4):113-115.
[39]Cao R,Han J,Deng Y,et al.Presence of high-titer neutralizing antibodies against enterovirus 71in intravenous immunoglobulin manufactured from Chinese donors[J].Clin Infect Dis,2010,50(1):125-126.
[40]Kiener TK,Jia Q,Meng T,et al.A novel universal neutralizing monoclonal antibody against enterovirus 71that targets the highly conserved“knob”region of VP3protein[J].PLoS Negl Trop Dis,2014,8(5):2895.
[41]Nagata N,Iwasaki T,Ami Y,et al.Differential localization of neurons susceptible to enterovirus 71and poliovirus type 1in the central nervous system of cynomolgus monkeys after intravenous inoculation[J].J Gen Virol,2004,85(10):2981-2989.
[42]McMinn PC.Recent advances in the molecular epidemiology and control of human enterovirus 71infection[J].Curr Opin Virol,2012,2(2):199-205.
[43]Mat-Rahim NA,Abubakar S.Human Enterovirus 71 DNA Vaccine Constructs Containing 5′UTR with Complete Internal Ribosome Entry Site Sequence Stimulated Improved Anti-Human Enterovirus 71Neutralizing Immune Responses[J].World Journal of Vaccines,2014,4(1):33-43.
[44]Wu CN,Lin YC,Fann C,et al.Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1vaccines and inactivated virus[J].Vaccine,2001,20(5-6):895-904.
[45]Zhu FC,Meng FY,Li JX,et al.Efficacy,safety,and immunology of an inactivated alum-adjuvant enterovirus 71vaccine in children in China:a multicentre,randomised,double-blind,placebo-controlled,phase 3trial[J].Lancet,2013,381(9882):2024-2032.
[46]Liu CC,Hwang CS,Yang WS,et al.Long-term immunogenicity studies of formalin-inactivated enterovirus 71whole-virion vaccine in macaques[J].PLoS ONE,2014,9(9):106756.
[47]Li R,Liu L,Mo Z,et al.An inactivated enterovirus 71vaccine in healthy children[J].N Engl J Med,2014,370(9):829-837.
[48]Roldo A,Mellado MC,Castilho LR,et al.Virus-like particles in vaccine development[J].Expert Rev Vaccines,2010,9(10):1149-1176.
[49]Chung CY,Chen CY,Lin SY,et al.Enterovirus 71virus-like particle vaccine:improved production conditions for enhanced yield[J].Vaccine,2010,28(43):6951-6957.
[50]Ku Z,Ye X,Huang X,et al.Neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71genotype C4inhibit infection at pre-and post-attachment steps[J].PLoS ONE,2013,8(2):57601.