H9N2亚型流感病毒浙江株的分子特征及Toll样受体介导的免疫损伤机制研究
|
摘要
1998年,香港地区报告首起人感染H9N2亚型禽流感病毒(简称H9N2病毒)病例以后,中国大陆也相继出现了人感染H9N2病毒病例。有研究表明,H9N2病毒在我国禽类从业人群中的感染率高达15%左右,并引起急性呼吸道感染症状。当前,H9N2病毒在我国家禽中持续传播,并出现了大规模基因重组,H9N2病毒已经成为人类呼吸道感染的重要病原之一,并作为一个潜在的流感大流行候选病毒而引起了全球的重视。
本研究对2011年100份来自浙江省家禽粪便样本进行了病毒分离,对获得的3株H9N2病毒进行全基因序列测定和进化分析；应用生物信息学软件,对网络数据库中H9N2病毒蛋白信息,进行了收集处理,构建一个实用、快速和高效的,能用于H9N2病毒生物学特征分析的蛋白数据分析库；分别在小鼠和人细胞水平上建立了感染模型,通过对Toll样受体(TLR)、NF-κB和IL-6表达水平之间的相互关系进行分析,初步探讨H9N2病毒对人类的致病机制。
首先,在2011年2月至6月期间,对来源于浙江省活禽市场中健康家禽的粪便样本进行收集,获得100份样本,并集中进行病毒分离,将获得的3株H9N2和9株H1亚型病毒株进行了基因扩增、序列测定和同源性分析。结果表明,浙江省家禽中存在H9N2、H1N2和H1N3病毒,均为欧亚系；H9N2病毒出现了对金刚烷胺类药物耐药的S31N突变位点。病毒进化分析表明,出现了H9N2和H1N2病毒重组现象,提示需加强家禽中流感病毒监测。本研究在中国范围内首次报道了H1N3亚型流感病毒,为H1亚型流感流行病学研究提供了重要资料。
应用生物信息学软件,对网络数据库中所有2013株H9N2病毒的蛋白信息,进行了全面收集和重新处理,建立了一个总共包含PB2、PB1、PB1-F2、PA、HA、 NP、NA、M1、M2、NS1和NS2等11个流感病毒蛋白的数据分析库,共包含了8948条序列信息。分析发现,禽类是H9N2病毒的主要自然宿主(占97.47%),主要分离于1997至2012年期间(占96.32%),主要来自亚洲地区(占96.37%)。有78.10%的H9N2病毒HA蛋白234位氨基酸为亮氨酸,具有与人类细胞优先结合的特性；有9.3%的H9N2病毒M2蛋白出现了对金刚烷胺类药物耐药的S31N突变点。该蛋白数据分析库,能快速进行有针对性的病毒生物特征分析,为有效预测H9N2病毒的感染性、致病性和耐药性提供参考。
为了评价H9N2病毒对哺乳动物的致病性,本研究首先在小鼠水平上建立了H9N2病毒诱导急性肺损伤的动物模型,对正常小鼠和受病毒感染小鼠的外周血和肺脏中的IL-6、SOD、TLR4、TLR7和NF-κB表达水平进行检测。结果表明,H9N2病毒浙江株A/chicken/Zhejiang/329/2011(Zj329)能感染小鼠,出现典型的急性临床症状。病毒感染小鼠后,小鼠肺组织细胞中TLR4、TLR7和NF-κB mRNA水平发生了明显上调,并引起外周血中炎性因子IL-6大量表达,在感染后第6d,这些参数值都达到最高。外周血中SOD表达水平在病毒感染后的2-6d内发生下降,在第4d达到最低值。
进一步在人肺A549细胞水平上建立了H9N2病毒(Zj329)的细胞感染模型,对Zj329病毒感染后细胞中和细胞上清中TLR4、TLR7、NF-κB和IL-6表达水平进行了检测。结果表明,Zj329病毒能有效感染A549细胞,出现典型的细胞病变现象。病毒感染A549细胞后,细胞中TLR4和TLR7mRNA水平都发生了明显上调,在病毒感染后12h达到最高值,同时NF-κB和IL-6表达活性也发生了明显上调,在24h内随时间增加而增强。
综上所述,本研究得出以下结论：
1、浙江省家禽中存在H9N2病毒,均为欧亚系。
2、首次发现H9N2和H1N2亚型流感病毒之间出现了重组现象。
3、H9N2病毒浙江株能有效感染小鼠和人A549细胞,发生肺脏损伤和细胞病变,TLR4、TLR7、NF-κB和IL-6介导了H9N2病毒感染哺乳动物而引起的免疫损伤过程。
总之,在近年来禽流感病毒感染人类时有发生的情况下,本研究构建的具有实用和快速的H9N2病毒蛋白数据分析库,为有效分析H9N2病毒的感染性、致病性和耐药性提供参考。通过本研究的开展,获得了H9N2病毒浙江株的相关信息,并在中国范围内首次报道了H1N3亚型流感病毒,发表了相关SCI论文3篇,不仅丰富了我国流感病毒的分子流行病学资料,也将为人感染禽流感防治工作的开展提供科学依据。同时,本研究对于阐明H9N2病毒在感染人类呼吸道过程中的致病机制,具有重要意义。
Since the first human case of H9N2influenza virus infection reported in Hong Kong in1998, infected patients were also reported in mainland of China. H9N2viruses have a high infection rate (about15%) in people occupied in poultry fields, and they can cause mild to moderate disease. Previous studies have shown that H9N2virus has continuously circulated in domestic poultry in China, and undergone extensive reassortment, which indicated that the virus may be an important pathogen of human respire system diseases and a candidate human pandemic strain.
For analyzing the molecular characteristics, several strains of H9N2influenza virus were isolated from poultry in Zhejiang Province in2011and whole genome sequencing and phylogenetic analyses were performed. By collecting the sequence information from the database of H9N2influenza virus in GenBank, we constructed a H9N2virus proteins date bank which was highly practical and efficient for analyzing H9N2virus biology characteristics. For exploring the mechanism of the H9N2virus infection in host cell, we studied the Toll-like receptor (TLR) induced immune responses by detecting levels of TLR4, TLR7, NF-κB and IL-6in mice and human cell lines.
One hundred cloacal swabs were collected from apparently healthy poultry in live poultry markets in Zhejiang Province, January to June, in2011. Whole genome sequencing and phylogenetic analyses of the isolated three H9N2and nine H1subtypes influenza virus strains were performed. The result showed that these viruses clustered in the Eurasian lineage of influenza viruses. These H9N2viruses had the molecular characteristics associated with amantadine resistance. The results of phylogenetic analysis indicate that a reassortment event has occurred between H9N2and H1N2viruses, and the continued surveillance of influenza viruses in poultry is necessary. To our knowledge, this is the first report on the genomic sequence and phylogenetic analysis of H1N3influenza viruses isolated from China, and it will provide important information for prevention of H1N3epidemic.
By collecting the sequence information from the database of H9N2influenza virus in GenBank and using Microsoft offices and BioEdit software, we constructed a H9N2viral proteins date bank including11viral proteins (PB2, PB1, PB1-F2, PA, HA, NP, NA, M1, M2, NS1and NS2proteins) and8948piece sequences. The result showed that the poultry is the natural hosts (97.47%) and mainly come from Asia (96.37%) from1997to2012(96.32%). About78.10%of the H9N2viruses have hunman-like receptor and9.3%of them have S31N mutation. This date bank is a practical and efficient tool for analyzing H9N2viral biology characteristics, such as infection ability and drug resistance, with high effective.
An appropriate animal model of acute respiratory distress syndrome (ARDS) infected by H9N2virus was made in mice, and the levels of IL-6, SOD, TLR4, TLR7and NF-κB in peripheral blood and lung were detected. The result showed that the H9N2virus (A/chicken/Zhejiang/329/2011, Zj329) isolated from Zhejiang had high virulence and pathogenicity in mice, characterized by a relatively acute clinical process in infected mice. The expression levels of TLR4, TLR7and NF-κB mRNA, and the content of IL-6were increased greatly in H9N2virus infected mice, and reached the highest level at day6after infection. The content of SOD were decreased greatly in H9N2virus infected mice from day2to day6, and reached the lowest level at day4after infection.
The levels of IL-6, SOD, TLR4, TLR7and NF-κB were detected in human A549cell after infection by H9N2virus (Zj329). The results showed that the H9N2virus infected A549cell presented a typical cytopathic effect (CPE). The expression levels of TLR4and TLR7mRNA, and the contents of NF-κB and IL-6were increased greatly in H9N2virus infected human A549cell, and reached the highest level at24hours after infection.
In summary, our data showed that,(i) the H9N2viruses prevailing in Zhejiang poultry were clustered in the Eurasian lineage of influenza viruses.(ii)Furthermore, a reassortment event was occurred between H9N2and H1N2viruses.(iii) H9N2viral infection induced typical ARDS in mice and typical CPE in human A549cells, and increased the levels of TLR4, TLR7, IL-6, and NF-κB. The H9N2viral proteins date bank can be used to analyze H9N2virus biology characteristics, such as infection and drug resistance, with high effectivity. Our results might give useful information to further studies of the pathogenesis of future potential avian H9N2disease in humans.
本研究对2011年100份来自浙江省家禽粪便样本进行了病毒分离,对获得的3株H9N2病毒进行全基因序列测定和进化分析；应用生物信息学软件,对网络数据库中H9N2病毒蛋白信息,进行了收集处理,构建一个实用、快速和高效的,能用于H9N2病毒生物学特征分析的蛋白数据分析库；分别在小鼠和人细胞水平上建立了感染模型,通过对Toll样受体(TLR)、NF-κB和IL-6表达水平之间的相互关系进行分析,初步探讨H9N2病毒对人类的致病机制。
首先,在2011年2月至6月期间,对来源于浙江省活禽市场中健康家禽的粪便样本进行收集,获得100份样本,并集中进行病毒分离,将获得的3株H9N2和9株H1亚型病毒株进行了基因扩增、序列测定和同源性分析。结果表明,浙江省家禽中存在H9N2、H1N2和H1N3病毒,均为欧亚系；H9N2病毒出现了对金刚烷胺类药物耐药的S31N突变位点。病毒进化分析表明,出现了H9N2和H1N2病毒重组现象,提示需加强家禽中流感病毒监测。本研究在中国范围内首次报道了H1N3亚型流感病毒,为H1亚型流感流行病学研究提供了重要资料。
应用生物信息学软件,对网络数据库中所有2013株H9N2病毒的蛋白信息,进行了全面收集和重新处理,建立了一个总共包含PB2、PB1、PB1-F2、PA、HA、 NP、NA、M1、M2、NS1和NS2等11个流感病毒蛋白的数据分析库,共包含了8948条序列信息。分析发现,禽类是H9N2病毒的主要自然宿主(占97.47%),主要分离于1997至2012年期间(占96.32%),主要来自亚洲地区(占96.37%)。有78.10%的H9N2病毒HA蛋白234位氨基酸为亮氨酸,具有与人类细胞优先结合的特性；有9.3%的H9N2病毒M2蛋白出现了对金刚烷胺类药物耐药的S31N突变点。该蛋白数据分析库,能快速进行有针对性的病毒生物特征分析,为有效预测H9N2病毒的感染性、致病性和耐药性提供参考。
为了评价H9N2病毒对哺乳动物的致病性,本研究首先在小鼠水平上建立了H9N2病毒诱导急性肺损伤的动物模型,对正常小鼠和受病毒感染小鼠的外周血和肺脏中的IL-6、SOD、TLR4、TLR7和NF-κB表达水平进行检测。结果表明,H9N2病毒浙江株A/chicken/Zhejiang/329/2011(Zj329)能感染小鼠,出现典型的急性临床症状。病毒感染小鼠后,小鼠肺组织细胞中TLR4、TLR7和NF-κB mRNA水平发生了明显上调,并引起外周血中炎性因子IL-6大量表达,在感染后第6d,这些参数值都达到最高。外周血中SOD表达水平在病毒感染后的2-6d内发生下降,在第4d达到最低值。
进一步在人肺A549细胞水平上建立了H9N2病毒(Zj329)的细胞感染模型,对Zj329病毒感染后细胞中和细胞上清中TLR4、TLR7、NF-κB和IL-6表达水平进行了检测。结果表明,Zj329病毒能有效感染A549细胞,出现典型的细胞病变现象。病毒感染A549细胞后,细胞中TLR4和TLR7mRNA水平都发生了明显上调,在病毒感染后12h达到最高值,同时NF-κB和IL-6表达活性也发生了明显上调,在24h内随时间增加而增强。
综上所述,本研究得出以下结论：
1、浙江省家禽中存在H9N2病毒,均为欧亚系。
2、首次发现H9N2和H1N2亚型流感病毒之间出现了重组现象。
3、H9N2病毒浙江株能有效感染小鼠和人A549细胞,发生肺脏损伤和细胞病变,TLR4、TLR7、NF-κB和IL-6介导了H9N2病毒感染哺乳动物而引起的免疫损伤过程。
总之,在近年来禽流感病毒感染人类时有发生的情况下,本研究构建的具有实用和快速的H9N2病毒蛋白数据分析库,为有效分析H9N2病毒的感染性、致病性和耐药性提供参考。通过本研究的开展,获得了H9N2病毒浙江株的相关信息,并在中国范围内首次报道了H1N3亚型流感病毒,发表了相关SCI论文3篇,不仅丰富了我国流感病毒的分子流行病学资料,也将为人感染禽流感防治工作的开展提供科学依据。同时,本研究对于阐明H9N2病毒在感染人类呼吸道过程中的致病机制,具有重要意义。
Since the first human case of H9N2influenza virus infection reported in Hong Kong in1998, infected patients were also reported in mainland of China. H9N2viruses have a high infection rate (about15%) in people occupied in poultry fields, and they can cause mild to moderate disease. Previous studies have shown that H9N2virus has continuously circulated in domestic poultry in China, and undergone extensive reassortment, which indicated that the virus may be an important pathogen of human respire system diseases and a candidate human pandemic strain.
For analyzing the molecular characteristics, several strains of H9N2influenza virus were isolated from poultry in Zhejiang Province in2011and whole genome sequencing and phylogenetic analyses were performed. By collecting the sequence information from the database of H9N2influenza virus in GenBank, we constructed a H9N2virus proteins date bank which was highly practical and efficient for analyzing H9N2virus biology characteristics. For exploring the mechanism of the H9N2virus infection in host cell, we studied the Toll-like receptor (TLR) induced immune responses by detecting levels of TLR4, TLR7, NF-κB and IL-6in mice and human cell lines.
One hundred cloacal swabs were collected from apparently healthy poultry in live poultry markets in Zhejiang Province, January to June, in2011. Whole genome sequencing and phylogenetic analyses of the isolated three H9N2and nine H1subtypes influenza virus strains were performed. The result showed that these viruses clustered in the Eurasian lineage of influenza viruses. These H9N2viruses had the molecular characteristics associated with amantadine resistance. The results of phylogenetic analysis indicate that a reassortment event has occurred between H9N2and H1N2viruses, and the continued surveillance of influenza viruses in poultry is necessary. To our knowledge, this is the first report on the genomic sequence and phylogenetic analysis of H1N3influenza viruses isolated from China, and it will provide important information for prevention of H1N3epidemic.
By collecting the sequence information from the database of H9N2influenza virus in GenBank and using Microsoft offices and BioEdit software, we constructed a H9N2viral proteins date bank including11viral proteins (PB2, PB1, PB1-F2, PA, HA, NP, NA, M1, M2, NS1and NS2proteins) and8948piece sequences. The result showed that the poultry is the natural hosts (97.47%) and mainly come from Asia (96.37%) from1997to2012(96.32%). About78.10%of the H9N2viruses have hunman-like receptor and9.3%of them have S31N mutation. This date bank is a practical and efficient tool for analyzing H9N2viral biology characteristics, such as infection ability and drug resistance, with high effective.
An appropriate animal model of acute respiratory distress syndrome (ARDS) infected by H9N2virus was made in mice, and the levels of IL-6, SOD, TLR4, TLR7and NF-κB in peripheral blood and lung were detected. The result showed that the H9N2virus (A/chicken/Zhejiang/329/2011, Zj329) isolated from Zhejiang had high virulence and pathogenicity in mice, characterized by a relatively acute clinical process in infected mice. The expression levels of TLR4, TLR7and NF-κB mRNA, and the content of IL-6were increased greatly in H9N2virus infected mice, and reached the highest level at day6after infection. The content of SOD were decreased greatly in H9N2virus infected mice from day2to day6, and reached the lowest level at day4after infection.
The levels of IL-6, SOD, TLR4, TLR7and NF-κB were detected in human A549cell after infection by H9N2virus (Zj329). The results showed that the H9N2virus infected A549cell presented a typical cytopathic effect (CPE). The expression levels of TLR4and TLR7mRNA, and the contents of NF-κB and IL-6were increased greatly in H9N2virus infected human A549cell, and reached the highest level at24hours after infection.
In summary, our data showed that,(i) the H9N2viruses prevailing in Zhejiang poultry were clustered in the Eurasian lineage of influenza viruses.(ii)Furthermore, a reassortment event was occurred between H9N2and H1N2viruses.(iii) H9N2viral infection induced typical ARDS in mice and typical CPE in human A549cells, and increased the levels of TLR4, TLR7, IL-6, and NF-κB. The H9N2viral proteins date bank can be used to analyze H9N2virus biology characteristics, such as infection and drug resistance, with high effectivity. Our results might give useful information to further studies of the pathogenesis of future potential avian H9N2disease in humans.
引文
[1]郭元吉,李建国.禽H9N2亚型流感病毒能感染人的发现.中华实验和临床病毒学杂志,1999,13(2)：105-8.
[2]Guan Y, Shortridge KF, Krauss S, et al. Molecular characterization of H9N2 influenza viruses:were they the donors of the "internal" genes of H5N1 viruses in Hong Kong? Proc Natl Acad Sci USA,1999,96(16):9363-7.
[3]柳洋,鲁恩洁,王玉林,等.广州市禽类从业人群禽流感病毒感染特征分析.中华流行病学杂志,2009,30(11)：1111-3.
[4]杨式芹,张彩云,谢剑锋,等.福建省2004-2008年职业暴露人群H9亚型禽流感病毒抗体血清流行病学调查.中国人兽共患病学报,2010,12：1145-7.
[5]Zhang P, Tang Y, Liu X, et al. A novel genotype H9N2 influenza virus possessing human H5N1 internal genomes has been circulating in poultry in eastern China since 1998. J Virol,2009,83(17):8428-38.
[6]Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A.2007,104(30):12479-81.
[7]Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008,133(2):235-49.
[8]徐明举,利凯,崔红玉.H3N2猪流感病毒诱导的小鼠急性肺损伤与SOD、NO、 MDA和OH变化的相关性.中国病理生理杂志,2011,27(4)：783-6,790.
[9]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors.Neuromolecular Med.2010,12(2): 149-63.
[10]Hopkins PA, Sriskandan S. Mammalian Toll-like receptors:to immunity and beyond. Clin Exp Immunol.2005,140(3):395-407.
[11]Perez DR, Lim W, Seiler JP, et al. Role of quail in the interspecies transmission of H9 influenza A viruses:molecular changes on HA that correspond to adaptation from ducks to chickens.J Virol.2003,77(5):3148-56.
[12]Guo CT, Takahashi N, Yagi H, et al. The quail and chicken intestine have sialyl-galactose sugar chains responsible for the binding of influenza A viruses to human type receptors. Glycobiology.2007,17(7):713-24.
[13]Kawaoka Y, Chambers TM, Sladen WL, et al. Is the gene pool of influenza viruses in shorebirds and gulls different from that in wild ducks? Virology,1988,163(1): 247-50.
[14]Liu M, He S, Walker D, et al. The influenza virus gene pool in a poultry market in South central china. Virology,2003,305(2):267-75.
[15]Nguyen DC, Uyeki TM, Jadhao S, et al. Isolation and characterization of avian influenza viruses, including highly pathogenic H5N1, from poultry in live bird markets in Hanoi, Vietnam, in 2001. J Virol,2005,79(7):4201-12.
[16]Cardona C, Yee K, Carpenter T. Are live bird markets reservoirs of avian influenza? Poult Sci,2009,88(4):856-9.
[17]Li KS, Xu KM, Peiris JS, et al. Characterization of H9 subtype influenza viruses from the ducks of China:a candidate for the next influenza pandemic in humans? J Virol,2003,77:6988-94.
[18]Wang M, Di B, Zhou DH, et al. Food markets with live birds as source of avian influenza. Emerg Infect Dis.2006,12(11):1773-5.
[19]Butt KM, Smith GJ, Chen H, et al. Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J Clin Microbiol.2005,43(11):5760-7.
[20]Lin Y P, Shaw M, Gregory V, et al. Avian-to-human transmission of H9N2 subtype influenza A viruses:Relationship between H9N2 and H5N1 human isolates. Proc Natl Acad Sci USA,2000,97:9654-8.
[21]仇保丰,刘武杰,彭大新,等.近年来华东地区家鸭中禽流感病毒的亚型分布.微生物学报,2008,48(10)：1290-4.
[22]Zhou H, Zhang A, Chen H, et al. Emergence of novel reassortant H3N2 influenza viruses among ducks in China.Arch Virol,2011,156(6):1045-8.
[23]Hoffmann E, Stech J, Guan Y, et al. Universal primer set for the full-length amplification of all influenza A viruses. Arch Virol,2001,146(12):2275-89.
[24]Chen J, Yang Z, Chen Q, et al. Characterization of H5N1 influenza A viruses isolated from domestic green-winged teal.Virus Genes,2009,38(1):66-73.
[25]Tamura K, Dudley J, Nei M, Kumar S.MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol,2007 24(8):1596-9.
[26]Jandaghi NZ, Azad TM, Naseri M, et al. Molecular and genetic characteristics of hemagglutinin and neuraminidase in Iranian 2009 pandemic influenza A(H1N1) viruses. Arch Virol,2010,155(5):717-21.
[27]Wu HB, Guo CT, Wu NP, et al. Genetic characterization of subtype H1 avian influenza viruses isolated from live poultry markets in Zhejiang Province, China, in 2011. Virus Genes.2012,44(3):441-9.
[28]Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 2004,73:1019-49.
[29]Aoki FY, Boivin G, Roberts N.Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther,2007,12:603-16.
[30]Zaraket H, Saito R, Suzuki Y, et al. Genetic makeup of amantadine-resistant and oseltamivir-resistant human influenza A/H1N1 viruses. J Clin Microbiol, 2010,48:1085-92.
[31]Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A (H3N2) and A (H1N1) viruses isolated worldwide. J Infect Dis,2007,196(2):249-57.
[32]Horimoto T, Ito T, Alexander DJ, et al. Cleavability of hemagglutinin from an extremely virulent strain of avian influenza virus containing a unique cleavage site sequence. J Vet Med Sci,1995,57(5):927-30.
[33]Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science.2004,303(5665):1838-42.
[34]Stevens J, Corper AL, Basler CF, et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science.2004, 303(5665):1866-70.
[35]Liu J, Bi Y, Qin K,et al. Emergence of European avian influenza virus-like H1N1 swine influenza A viruses in China. J Clin Microbiol,2009,47(8):2643-6.
[36]Bateman AC, Busch MG, Karasin Al, et al. Amino acid 226 in the hemagglutinin of H4N6 influenza virus determines binding affinity for alpha2,6-linked sialic acid and infectivity levels in primary swine and human respiratory epithelial cells. J Virol,2008,82:8204-9.
[37]Guan Y, Shortridge KF, Krauss S, et al.H9N2 influenza viruses possessing H5N1-like internal genomes continue to circulate in poultry in southeastern China. J Virol.2000,74(20):9372-80.
[38]Webster RG, Bean WJ, Gorman OT, et al. Evolution and ecology of influenza A viruses. Microbiol Rev,1992,56:152-79.
[39]Hatchette TF, Walker D, Johnson C, et al. Influenza A viruses in feral Canadian ducks:extensive reassortment in nature. J Gen Virol.2004,85(Pt 8):2327-37.
[40]Webster RG, Guan Y, Peiris M, et al. Characterization of H5N1 influenza viruses that continue to circulate in geese in southeastern China. J Virol. 2002,76(1):118-26.
[41]Jeong OM, Kim YJ, Choi JG, et al. Genetic characterization of H1 avian influenza viruses isolated from migratory birds and domestic ducks in Korea. Virus Genes, 2011,42(1):55-63.
[42]Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus.Nature,2009,459:931-9.
[43]沃恩康,吴海波,郭潮潭,等.甲型H1N1流感病毒基因组序列分析及其特性研 究.国际流行病学传染病学杂志,2009,36(3)：149-53.
[44]Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev.2001,14(1):129-49.
[45]Perez DR, Webby RJ, Hoffmann E, et al. Land-based birds as potential disseminators of avian mammalian reassortant influenza A viruses. Avian Dis. 2003,47(3 Suppl):1114-7.
[46]Alexander DJ. A review of avian influenza in different bird species. Vet Microbiol. 2000,74(1-2):3-13.
[47]Cong YL, Pu J, Liu QF, et al. Antigenic and genetic characterization of H9N2 swine influenza viruses in China. J Gen Virol.2007,88(Pt7):2035-41.
[48]Dong G, Luo J, Zhang H, et al. Phylogenetic diversity and genotypical complexity of H9N2 influenza A viruses revealed by genomic sequence analysis. PLoS One. 2011,6(2):e17212.
[49]Moon HJ, Song MS, Cruz DJ, et al. Active reassortment of H9 influenza viruses between wild birds and live-poultry markets in Korea. Arch Virol,2010,155(2): 229-41.
[50]Dong G, Xu C, Wang C, et al. Reassortant H9N2 influenza viruses containing H5N1-like PB1 genes isolated from black-billed magpies in Southern China. PLoS One.2011,6(9):e25808.
[51]Zhang Y, Teng Q, Ren C, et al. Complete Genome Sequence of a Novel Reassortant H11N2 Avian Influenza Virus Isolated from a Live Poultry Market in Eastern China. J Virol.2012,86(22):12443.
[52]Teng Q, Hu T, Li X, et al. Complete Genome Sequence of an H3N2 Avian Influenza Virus Isolated from a Live Poultry Market in Eastern China. J Virol.2012, 86(21):11944.
[53]Kawaoka Y, Webster R G.Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A.1988,85(2):324-8.
[54]Matrosovich MN, Krauss S, Webster RG. H9N2 influenza A viruses from poultry in Asia have human virus-like receptor specificity. Virology.2001,281(2):156-62.
[55]Bao Y, Bolotov P, Dernovoy D, et al. The influenza virus resource at the National Center for Biotechnology Information. J Virol.2008,82(2):596-601.
[56]Hall TA. BioEdit:a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser.1999,41:95-8.
[57]Tippmann HF. Analysis for free:comparing programs for sequence analysis. Brief Bioinform.2004,5(1):82-7.
[58]Kobasa D, Kodihalli S, Luo M, et al. Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J Virol.1999,73(8): 6743-51.
[59]Subbarao EK, London W, Murphy BR. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol.1993,67(4):1761-4.
[60]Gabriel G, Dauber B, Wolff T,et al. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005,102(51):18590-5.
[61]Wang J, Sun Y, Xu Q, et al. Mouse-adapted H9N2 influenza A virus PB2 protein M147L and E627K mutations are critical for high virulence.PLoS One. 2012,7(7):e40752.
[62]Mok CK, Yen HL, Yu MY, et al. Amino acid residues 253 and 591 of the PB2 protein of avian influenza virus A H9N2 contribute to mammalian pathogenesis. J Virol.2011,85(18):9641-5.
[63]Conenello GM, Palese P. Influenza A virus PB1-F2:a small protein with a big punch. Cell Host Microbe.2007,2(4):207-9.
[64]Zhu Q, Yang H, Chen W, et al. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol.2008,82(1):220-8.
[65]Twu KY, Kuo RL, Marklund J, Krug RM. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol. 2007,81(15):8112-21.
[66]Jiao P, Tian G, Li Y, et al. A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol.2008,82(3):1146-54.
[67]Masuda H, Suzuki H, Oshitani H, et al. Incidence of amantadine-resistant influenza A viruses in sentinel surveillance sites and nursing homes in Niigata, Japan. Micrebiol Immunol,2000,44(10):833-9.
[68]Aoki FY, Boivin G, Roberts N.Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther.2007,12(4 Pt B):603-16.
[69]Abed Y, Nehme B, Baz M, Boivin G. Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res.2008,77(2):163-6.
[70]Richard M, Ferraris O, Erny A, et al. Combinatorial effect of two framework mutations (E119V and I222L) in the neuraminidase active site of H3N2 influenza virus on resistance to oseltamivir. Antimicrob Agents Chemother. 2011,55(6):2942-52.
[71]Zurcher T, Yates PJ, Daly J, et al. Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro.J Antimicrob Chemother.2006,58(4):723-32.
[72]McKimm-Breschkin JL, Sahasrabudhe A, et al. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol.1998,72(3):2456-62.
[73]Dong G, Luo J, Zhang H, et al. Phylogenetic diversity and genotypical complexity of H9N2 influenza A viruses revealed by genomic sequence analysis. PLoS One.2011,6(2):e17212.
[74]郭潮潭主编.流行性感冒.北京：科学出版社,2010.4,p76-84.
[75]郭元吉,温乐英,王敏,等.我国猪群中H9N2亚型毒株HA和NA基因特性的研究.中华实验和临床病毒学杂志,2004,18(1)：7-11.
[76]Yu H, Hua RH, Wei TC, et al. Isolation and genetic characterization of avian origin H9N2 influenza viruses from pigs in China.Vet Microbiol,2008,131(1-2):82-92.
[77]Cong YL, Wang CF, Yan CM, et al. Swine infection with H9N2 influenza viruses in China in 2004. Virus Genes.2008,36(3):461-9.
[78]Matrosovich MN, Krauss S, Webster RG. H9N2 influenza A viruses from poultry in Asia have human virus-like receptor specificity.Virology.2001,281 (2):156-62.
[79]Matsuoka Y, Swayne DE, Thomas C, et al. Neuraminidase stalk length and additional glycosylation of the hemagglutinin influence the virulence of influenza H5N1 viruses for mice. J Virol.2009,83(9):4704-8.
[80]Sorrell EM, Song H, Pena L, Perez DR.A 27-amino-acid deletion in the neuraminidase stalk supports replication of an avian H2N2 influenza A virus in the respiratory tract of chickens. J Virol.2010,84(22):11831-40.
[81]Chockalingam AK, Hickman D, Pena L, et al. Deletions in the neuraminidase stalk region of H2N2 and H9N2 avian influenza virus subtypes do not affect postinfluenza secondary bacterial pneumonia. J Virol.2012,86(7):3564-73.
[82]Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology,1999,258(1):1-20.
[83]Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev.2001,14(1):129-49.
[84]de Wit E, Kawaoka Y, de Jong MD, Fouchier RA. Pathogenicity of highly pathogenic avian influenza virus in mammals. Vaccine.2008,26 Suppl 4:D54-8.
[85]Zhang Z, Hu S, Li Z, et al. Multiple amino acid substitutions involved in enhanced pathogenicity of LPAIH9N2 in mice. Infect Genet Evol.2011,11(7):1790-7.
[86]Ping J, Dankar SK, Forbes NE, et al. PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus.J Virol.2010,84(20):10606-18.
[87]Zamarin D, Garcia-Sastre A, Xiao X, et al. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog.2005,1(1):e4.
[88]Conenello GM, Tisoncik JR, Rosenzweig E, et al. A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo. J Virol.2011,85(2):652-62.
[89]Conenello GM, Zamarin D, Perrone LA, et al. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog.2007,3(10):1414-21.
[90]Seo SH, Hoffmann E, Webster RG Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med.2002,8(9):950-4.
[91]Dankar SK, Wang S, Ping J, et al. Influenza A virus NS1 gene mutations F103L and M106I increase replication arid virulence. Virol J.2011,8:13.
[92]Stiver G The treatment of influenza with antiviral drugs.CMAJ.2001,45(12): 3403-8.
[93]Zaraket H, Saito R, Suzuki Y,et al. Genetic makeup of amantadine- resistant and oseltamivir-resistant human influenza A/H1N1 viruses. J Clin Microbiol.2010,48 (4):1085-92.
[94]Le QM, Kiso M, Someya K, et al. Avian flu:isolation of drug-resistant H5N1 virus. Nature.2005,437(7062):1108.
[95]Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997,388(6640):394-7.
[96]Barton GM, Medzhitov R. Toll-like receptors and their ligands. Curr Top Microbiol Immunol.2002,270:81-92.
[97]Sloane JA, Blitz D, Margolin Z, et al. A clear and present danger:endogenous ligands of Toll-like receptors. Neuromolecular Med.2010,12(2):149-63.
[98]Hopkins PA, Sriskandan S. Mammalian Toll-like receptors:to immunity and beyond. Clin Exp Immunol.2005,140(3):395-407.
[99]Xie XH, Law HK, Wang LJ, et al. Lipopolysaccharide induces IL-6 production in respiratory syncytial virus-infected airway epithelial cells through the toll-like receptor 4 signaling pathway. Pediatr Res.2009,65(2):156-62.
[100]Jeisy-Scott V, Davis WG, Patel JR, et al. Increased MDSC accumulation and Th2 biased response to influenza A virus infection in the absence of TLR7 in mice. PLoS One.2011,6(9):e25242.
[101]Deng G, Bi J, Kong F, et al. Acute respiratory distress syndrome induced by H9N2 virus in mice. Arch Virol,2010,155(2):187-95.
[102]Kimura Y. Cytokines and chemokines induced by influenza virus infection. Nihon Rinsho,2006,64(10):1822-7.
[103]Chan MC, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells.Respir Res,2005,6:135.
[104]吕卫华,黄卫良.急性支气管肺炎患儿血清SOD及相关细胞因子测定的意义.放射免疫学杂志,2010,23(3)：250-3.
[105]Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science.2004,303(5663): 1529-31.
[106]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011,81(7):825-37.
[107]Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.J Virol.2005,79(11):7269-72.
[108]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors.Neuromolecular Med.2010,12(2): 149-63.
[109]Henrick BM, Nag K, Yao XD, et al. Milk matters:soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLoS One.2012,7(7):e40138.
[110]Yu WC, Chan RW, Wang J, et al. Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. J Virol.2011,85(14):6844-55.
[111]Chan MC, Chan RW, Yu WC, et al.Influenza H5N1 virus infection of polarized human alveolar epithelial cells and lung microvascular endothelial cells. Respir Res.2009,10:102.
[112]窦颖,赵晓东,赵耀.人偏肺病毒感染人肺上皮细胞后Toll样受体的表达及其功能.中华微生物学和免疫学杂志,2009,12：1122-7.
[113]黄升海,魏伟,云云.呼吸道合胞病毒感染上调Toll样受体7和3基因的早期表达.微生物学报,2009,49(2)：239-45.
[114]黄丽,郭显蓉,屠宴会,等.A549细胞和Hep-2细胞表面糖链类型鉴定及其与H5N1型禽流感病毒结合的特性.基础医学与临床,2010,12：1318-24.
[115]牛旭艳,张春晶,顾立刚.毒热平注射液对甲型流感病毒H3N2体外感染细胞中TLR7信号通路的影响.中华中医药杂志,2010,2：194-7.
[116]Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog.2006,2(6):e53.
[117]Qu B, Li X, Gao W, et al. Human intestinal epithelial cells are susceptible to influenza virus subtype H9N2.Virus Res.2012,163(1):151-9.
[1]Carty M, Bowie AG. Recent insights into the role of Toll-like receptors in viral infection. Clin Exp Immunol.2010,161(3):397-406.
[2]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors. Neuromolecular Med.2010,12(2): 149-63.
[3]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011,81 (7):825-37.
[4]Rallabhandi P, Phillips RL, Boukhvalova MS, et al.Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. MBio.2012,3(4). pii:e00218-12.
[5]Xie XH, Law HK, Wang LJ, et al. Lipopolysaccharide induces IL-6 production in respiratory syncytial virus-infected airway epithelial cells through the toll-like receptor 4 signaling pathway. Pediatr Res.2009,65(2):156-62.
[6]Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol.2009,83(3):1492-1500.
[7]Klein Klouwenberg P, Tan L, Werkman W, et al. The role of Toll-like receptors in regulating the immune response against respiratory syncytial virus. Crit Rev Immunol.2009,29(6):531-50.
[8]Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol.2009,83(3):1492-500.
[9]Davidson S, Kaiko G, Loh Z, et al. Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway. J Immunol.2011,186(10):5938-48.
[10]van der Sluijs KF, van Elden L, Nijhuis M, et al. Toll-like receptor 4 is not involved in host defense against respiratory tract infection with Sendai virus. Immunol Lett. 2003,89(2-3):201-6.
[11]Wei XQ, Guo YW, Liu JJ, et al. The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B. Clin Invest Med.2008,31(3): E123-30.
[12]Chen Z, Cheng Y, Xu Y, et al. Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol 2008,128:400-8.
[13]Wu J, Meng Z, Jiang M, et al. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology.2010,129(3): 363-74.
[14]Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.J Virol.2005,79(11):7269-72.
[15]Abe T, Fukuhara T, Wen X, et al. CD44 participates in IP-10 induction in cells in which hepatitis C virus RNA is replicating, through an interaction with Toll-like receptor 2 and hyaluronan. J Virol.2012,86(11):6159-70.
[16]Chang S, Dolganiuc A, Szabo G. Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol.2007,82(3):479-87.
[17]Guo J, Loke J, Zheng F, et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology.2009,49(3):960-8.
[18]Macdonald A, Harris M. Hepatitis C virus NS5A:tales of a promiscuous protein. J Gen Virol.2004,85(Pt 9):2485-502.
[19]Machida K, Tsukamoto H, Mkrtchyan H, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc NatI Acad Sci USA.2009,106(5):1548-53.
[20]Sundstrom JB, Little DM, Villinger F, et al. Signaling through Toll-like receptors triggers HIV-1 replication in latently infected mast cells. J Immunol.2004,172(7):4391-401.
[21]Crane M, Visvanathan K, Lewin SR. HIV Infection and TLR Signalling in the Liver. Gastroenterol Res Pract.2012,2012:473925.
[22]Pine SO, McElrath MJ, Bochud PY. Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS.2009,23(18):2387-95.
[23]Rassa JC, Meyers JL, Zhang Y, et al. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA.2002,99(4):2281-6.
[24]Lagos D, Vart RJ, Gratrix F, et al. Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe.2008,4(5):470-83.
[25]Ahmad H, Gubbels R, Ehlers E, et al. Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). J Biol Chem.2011,286(10):7865-72.
[26]Li H, Li X, Wei Y, et al. HSV-2 induces TLRs and NF-kappaB-dependent cytokines in cervical epithelial cells.Biochem Biophys Res Commun.2009,379(3): 686-90.
[27]S(?)rensen LN, Reinert LS, Malmgaard L, et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol.2008,181(12): 8604-12.
[28]Fairweather D, Yusung S, Frisancho S, et al. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol.2003,170(9):4731-7.
[29]Triantafilou K, Triantafilou M. Coxsackievirus B4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4. J Virol.2004,78(20): 11313-20.
[30]Zhu J, Martinez J, Huang X, Yang Y. Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta. Blood.2007,109(2):619-25.
[31]Martinez J, Huang X, Yang Y. Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection. PLoS Pathog. 2010,6(3):e1000811.
[32]Hutchens MA, Luker KE, Sonstein J, et al. Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection. PLoS Pathog.2008,4(9):e1000153.
[33]Samuelsson C, Hausmann J, Lauterbach H, et al. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. J Clin Invest.2008,118(5):1776-84.
[34]Georgel P, Jiang Z, Kunz S, et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology. 2007,362(2):304-13.
[35]Schabbauer G, Luyendyk J, Crozat K, et al. TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages. Mol Immunol.2008,45(10):2790-6.
[36]Yokota S, Okabayashi T, Yokosawa N, Fujii N. Measles virus P protein suppresses Toll-like receptor signal through up-regulation of ubiquitin-modifying enzyme A20. FASEB J.2008,22(1):74-83.
[37]Ovsyannikova IG, Haralambieva IH, Vierkant RA, et al. The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity. Hum Genet.2011,130(4):547-61.
[38]Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A,2007, 104(30):12479-81.
[39]Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science.2004,303(5663): 1529-31.
[40]Ramos I, Fernandez-Sesma A. Cell receptors for influenza a viruses and the innate immune response. Front Microbiol.2012,3:117.
[41]Jeisy-Scott V, Davis WG, Patel JR, et al. Increased MDSC accumulation and Th2 biased response to influenza A virus infection in the absence of TLR7 in mice. PLoS One.2011,6(9):e25242.
[42]Maschalidi S, Hassler S, Blanc F, et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog. 2012;8(8):e1002841.
[43]Karnam G, Rygiel TP, Raaben M, et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS Pathog.2012,8(5):e1002710.
[44]Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog.2006,2(6):e53.
[45]Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell.2008,133(2): 235-49.
[46]Nang NT, Lee JS, Song BM, et al. Induction of inflammatory cytokines and toll-like receptors in chickens infected with avian H9N2 influenza virus. Vet Res.2011,42(1):64.
[47]Hayashi T, Hiromoto Y, Chaichoune K, et al. Host cytokine responses of pigeons infected with highly pathogenic Thai avian influenza viruses of subtype H5N1 isolated from wild birds. PLoS One.2011,6(8):e23103.
[48]Zhou S, Halle A, Kurt-Jones EA, et al. Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses. J Neuroimmunol.2008,194(1-2):70-82.
[49]Gaudreault E, Fiola S, Olivier M, Gosselin J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J Virol.2007,81(15):8016-24.
[50]Lai Y, Yi G, Chen A, et al. Viral double-strand RNA-binding proteins can enhance innate immune signaling by toll-like Receptor 3. PLoS One.2011,6(10):e25837.
[51]Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med.2004,10(12): 1366-73.
[52]Pott J, Stockinger S, Torow N, et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 2012,8(5):e1002670.
[53]Kindberg E, Vene S, Mickiene A, et al. A functional Toll-like receptor 3 gene (TLR3) may be a risk factor for tick-borne encephalitis virus (TBEV) infection. J Infect Dis.2011,203(4):523-8.
[54]Wang Q, Miller DJ, Bowman ER, et al. MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness. PLoS Pathog.2011,7(5):e1002070.
[55]Browne EP. Toll-like receptor 7 controls the anti-retroviral germinal center response. PLoS Pathog.2011,7(10):e1002293.
[56]Henrick BM, Nag K, Yao XD, et al. Milk matters:soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLoS One.2012,7(7):e40138.
[2]Guan Y, Shortridge KF, Krauss S, et al. Molecular characterization of H9N2 influenza viruses:were they the donors of the "internal" genes of H5N1 viruses in Hong Kong? Proc Natl Acad Sci USA,1999,96(16):9363-7.
[3]柳洋,鲁恩洁,王玉林,等.广州市禽类从业人群禽流感病毒感染特征分析.中华流行病学杂志,2009,30(11)：1111-3.
[4]杨式芹,张彩云,谢剑锋,等.福建省2004-2008年职业暴露人群H9亚型禽流感病毒抗体血清流行病学调查.中国人兽共患病学报,2010,12：1145-7.
[5]Zhang P, Tang Y, Liu X, et al. A novel genotype H9N2 influenza virus possessing human H5N1 internal genomes has been circulating in poultry in eastern China since 1998. J Virol,2009,83(17):8428-38.
[6]Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A.2007,104(30):12479-81.
[7]Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008,133(2):235-49.
[8]徐明举,利凯,崔红玉.H3N2猪流感病毒诱导的小鼠急性肺损伤与SOD、NO、 MDA和OH变化的相关性.中国病理生理杂志,2011,27(4)：783-6,790.
[9]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors.Neuromolecular Med.2010,12(2): 149-63.
[10]Hopkins PA, Sriskandan S. Mammalian Toll-like receptors:to immunity and beyond. Clin Exp Immunol.2005,140(3):395-407.
[11]Perez DR, Lim W, Seiler JP, et al. Role of quail in the interspecies transmission of H9 influenza A viruses:molecular changes on HA that correspond to adaptation from ducks to chickens.J Virol.2003,77(5):3148-56.
[12]Guo CT, Takahashi N, Yagi H, et al. The quail and chicken intestine have sialyl-galactose sugar chains responsible for the binding of influenza A viruses to human type receptors. Glycobiology.2007,17(7):713-24.
[13]Kawaoka Y, Chambers TM, Sladen WL, et al. Is the gene pool of influenza viruses in shorebirds and gulls different from that in wild ducks? Virology,1988,163(1): 247-50.
[14]Liu M, He S, Walker D, et al. The influenza virus gene pool in a poultry market in South central china. Virology,2003,305(2):267-75.
[15]Nguyen DC, Uyeki TM, Jadhao S, et al. Isolation and characterization of avian influenza viruses, including highly pathogenic H5N1, from poultry in live bird markets in Hanoi, Vietnam, in 2001. J Virol,2005,79(7):4201-12.
[16]Cardona C, Yee K, Carpenter T. Are live bird markets reservoirs of avian influenza? Poult Sci,2009,88(4):856-9.
[17]Li KS, Xu KM, Peiris JS, et al. Characterization of H9 subtype influenza viruses from the ducks of China:a candidate for the next influenza pandemic in humans? J Virol,2003,77:6988-94.
[18]Wang M, Di B, Zhou DH, et al. Food markets with live birds as source of avian influenza. Emerg Infect Dis.2006,12(11):1773-5.
[19]Butt KM, Smith GJ, Chen H, et al. Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J Clin Microbiol.2005,43(11):5760-7.
[20]Lin Y P, Shaw M, Gregory V, et al. Avian-to-human transmission of H9N2 subtype influenza A viruses:Relationship between H9N2 and H5N1 human isolates. Proc Natl Acad Sci USA,2000,97:9654-8.
[21]仇保丰,刘武杰,彭大新,等.近年来华东地区家鸭中禽流感病毒的亚型分布.微生物学报,2008,48(10)：1290-4.
[22]Zhou H, Zhang A, Chen H, et al. Emergence of novel reassortant H3N2 influenza viruses among ducks in China.Arch Virol,2011,156(6):1045-8.
[23]Hoffmann E, Stech J, Guan Y, et al. Universal primer set for the full-length amplification of all influenza A viruses. Arch Virol,2001,146(12):2275-89.
[24]Chen J, Yang Z, Chen Q, et al. Characterization of H5N1 influenza A viruses isolated from domestic green-winged teal.Virus Genes,2009,38(1):66-73.
[25]Tamura K, Dudley J, Nei M, Kumar S.MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol,2007 24(8):1596-9.
[26]Jandaghi NZ, Azad TM, Naseri M, et al. Molecular and genetic characteristics of hemagglutinin and neuraminidase in Iranian 2009 pandemic influenza A(H1N1) viruses. Arch Virol,2010,155(5):717-21.
[27]Wu HB, Guo CT, Wu NP, et al. Genetic characterization of subtype H1 avian influenza viruses isolated from live poultry markets in Zhejiang Province, China, in 2011. Virus Genes.2012,44(3):441-9.
[28]Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 2004,73:1019-49.
[29]Aoki FY, Boivin G, Roberts N.Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther,2007,12:603-16.
[30]Zaraket H, Saito R, Suzuki Y, et al. Genetic makeup of amantadine-resistant and oseltamivir-resistant human influenza A/H1N1 viruses. J Clin Microbiol, 2010,48:1085-92.
[31]Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A (H3N2) and A (H1N1) viruses isolated worldwide. J Infect Dis,2007,196(2):249-57.
[32]Horimoto T, Ito T, Alexander DJ, et al. Cleavability of hemagglutinin from an extremely virulent strain of avian influenza virus containing a unique cleavage site sequence. J Vet Med Sci,1995,57(5):927-30.
[33]Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science.2004,303(5665):1838-42.
[34]Stevens J, Corper AL, Basler CF, et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science.2004, 303(5665):1866-70.
[35]Liu J, Bi Y, Qin K,et al. Emergence of European avian influenza virus-like H1N1 swine influenza A viruses in China. J Clin Microbiol,2009,47(8):2643-6.
[36]Bateman AC, Busch MG, Karasin Al, et al. Amino acid 226 in the hemagglutinin of H4N6 influenza virus determines binding affinity for alpha2,6-linked sialic acid and infectivity levels in primary swine and human respiratory epithelial cells. J Virol,2008,82:8204-9.
[37]Guan Y, Shortridge KF, Krauss S, et al.H9N2 influenza viruses possessing H5N1-like internal genomes continue to circulate in poultry in southeastern China. J Virol.2000,74(20):9372-80.
[38]Webster RG, Bean WJ, Gorman OT, et al. Evolution and ecology of influenza A viruses. Microbiol Rev,1992,56:152-79.
[39]Hatchette TF, Walker D, Johnson C, et al. Influenza A viruses in feral Canadian ducks:extensive reassortment in nature. J Gen Virol.2004,85(Pt 8):2327-37.
[40]Webster RG, Guan Y, Peiris M, et al. Characterization of H5N1 influenza viruses that continue to circulate in geese in southeastern China. J Virol. 2002,76(1):118-26.
[41]Jeong OM, Kim YJ, Choi JG, et al. Genetic characterization of H1 avian influenza viruses isolated from migratory birds and domestic ducks in Korea. Virus Genes, 2011,42(1):55-63.
[42]Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus.Nature,2009,459:931-9.
[43]沃恩康,吴海波,郭潮潭,等.甲型H1N1流感病毒基因组序列分析及其特性研 究.国际流行病学传染病学杂志,2009,36(3)：149-53.
[44]Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev.2001,14(1):129-49.
[45]Perez DR, Webby RJ, Hoffmann E, et al. Land-based birds as potential disseminators of avian mammalian reassortant influenza A viruses. Avian Dis. 2003,47(3 Suppl):1114-7.
[46]Alexander DJ. A review of avian influenza in different bird species. Vet Microbiol. 2000,74(1-2):3-13.
[47]Cong YL, Pu J, Liu QF, et al. Antigenic and genetic characterization of H9N2 swine influenza viruses in China. J Gen Virol.2007,88(Pt7):2035-41.
[48]Dong G, Luo J, Zhang H, et al. Phylogenetic diversity and genotypical complexity of H9N2 influenza A viruses revealed by genomic sequence analysis. PLoS One. 2011,6(2):e17212.
[49]Moon HJ, Song MS, Cruz DJ, et al. Active reassortment of H9 influenza viruses between wild birds and live-poultry markets in Korea. Arch Virol,2010,155(2): 229-41.
[50]Dong G, Xu C, Wang C, et al. Reassortant H9N2 influenza viruses containing H5N1-like PB1 genes isolated from black-billed magpies in Southern China. PLoS One.2011,6(9):e25808.
[51]Zhang Y, Teng Q, Ren C, et al. Complete Genome Sequence of a Novel Reassortant H11N2 Avian Influenza Virus Isolated from a Live Poultry Market in Eastern China. J Virol.2012,86(22):12443.
[52]Teng Q, Hu T, Li X, et al. Complete Genome Sequence of an H3N2 Avian Influenza Virus Isolated from a Live Poultry Market in Eastern China. J Virol.2012, 86(21):11944.
[53]Kawaoka Y, Webster R G.Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A.1988,85(2):324-8.
[54]Matrosovich MN, Krauss S, Webster RG. H9N2 influenza A viruses from poultry in Asia have human virus-like receptor specificity. Virology.2001,281(2):156-62.
[55]Bao Y, Bolotov P, Dernovoy D, et al. The influenza virus resource at the National Center for Biotechnology Information. J Virol.2008,82(2):596-601.
[56]Hall TA. BioEdit:a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser.1999,41:95-8.
[57]Tippmann HF. Analysis for free:comparing programs for sequence analysis. Brief Bioinform.2004,5(1):82-7.
[58]Kobasa D, Kodihalli S, Luo M, et al. Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J Virol.1999,73(8): 6743-51.
[59]Subbarao EK, London W, Murphy BR. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol.1993,67(4):1761-4.
[60]Gabriel G, Dauber B, Wolff T,et al. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005,102(51):18590-5.
[61]Wang J, Sun Y, Xu Q, et al. Mouse-adapted H9N2 influenza A virus PB2 protein M147L and E627K mutations are critical for high virulence.PLoS One. 2012,7(7):e40752.
[62]Mok CK, Yen HL, Yu MY, et al. Amino acid residues 253 and 591 of the PB2 protein of avian influenza virus A H9N2 contribute to mammalian pathogenesis. J Virol.2011,85(18):9641-5.
[63]Conenello GM, Palese P. Influenza A virus PB1-F2:a small protein with a big punch. Cell Host Microbe.2007,2(4):207-9.
[64]Zhu Q, Yang H, Chen W, et al. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol.2008,82(1):220-8.
[65]Twu KY, Kuo RL, Marklund J, Krug RM. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol. 2007,81(15):8112-21.
[66]Jiao P, Tian G, Li Y, et al. A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol.2008,82(3):1146-54.
[67]Masuda H, Suzuki H, Oshitani H, et al. Incidence of amantadine-resistant influenza A viruses in sentinel surveillance sites and nursing homes in Niigata, Japan. Micrebiol Immunol,2000,44(10):833-9.
[68]Aoki FY, Boivin G, Roberts N.Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther.2007,12(4 Pt B):603-16.
[69]Abed Y, Nehme B, Baz M, Boivin G. Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res.2008,77(2):163-6.
[70]Richard M, Ferraris O, Erny A, et al. Combinatorial effect of two framework mutations (E119V and I222L) in the neuraminidase active site of H3N2 influenza virus on resistance to oseltamivir. Antimicrob Agents Chemother. 2011,55(6):2942-52.
[71]Zurcher T, Yates PJ, Daly J, et al. Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro.J Antimicrob Chemother.2006,58(4):723-32.
[72]McKimm-Breschkin JL, Sahasrabudhe A, et al. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol.1998,72(3):2456-62.
[73]Dong G, Luo J, Zhang H, et al. Phylogenetic diversity and genotypical complexity of H9N2 influenza A viruses revealed by genomic sequence analysis. PLoS One.2011,6(2):e17212.
[74]郭潮潭主编.流行性感冒.北京：科学出版社,2010.4,p76-84.
[75]郭元吉,温乐英,王敏,等.我国猪群中H9N2亚型毒株HA和NA基因特性的研究.中华实验和临床病毒学杂志,2004,18(1)：7-11.
[76]Yu H, Hua RH, Wei TC, et al. Isolation and genetic characterization of avian origin H9N2 influenza viruses from pigs in China.Vet Microbiol,2008,131(1-2):82-92.
[77]Cong YL, Wang CF, Yan CM, et al. Swine infection with H9N2 influenza viruses in China in 2004. Virus Genes.2008,36(3):461-9.
[78]Matrosovich MN, Krauss S, Webster RG. H9N2 influenza A viruses from poultry in Asia have human virus-like receptor specificity.Virology.2001,281 (2):156-62.
[79]Matsuoka Y, Swayne DE, Thomas C, et al. Neuraminidase stalk length and additional glycosylation of the hemagglutinin influence the virulence of influenza H5N1 viruses for mice. J Virol.2009,83(9):4704-8.
[80]Sorrell EM, Song H, Pena L, Perez DR.A 27-amino-acid deletion in the neuraminidase stalk supports replication of an avian H2N2 influenza A virus in the respiratory tract of chickens. J Virol.2010,84(22):11831-40.
[81]Chockalingam AK, Hickman D, Pena L, et al. Deletions in the neuraminidase stalk region of H2N2 and H9N2 avian influenza virus subtypes do not affect postinfluenza secondary bacterial pneumonia. J Virol.2012,86(7):3564-73.
[82]Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology,1999,258(1):1-20.
[83]Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev.2001,14(1):129-49.
[84]de Wit E, Kawaoka Y, de Jong MD, Fouchier RA. Pathogenicity of highly pathogenic avian influenza virus in mammals. Vaccine.2008,26 Suppl 4:D54-8.
[85]Zhang Z, Hu S, Li Z, et al. Multiple amino acid substitutions involved in enhanced pathogenicity of LPAIH9N2 in mice. Infect Genet Evol.2011,11(7):1790-7.
[86]Ping J, Dankar SK, Forbes NE, et al. PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus.J Virol.2010,84(20):10606-18.
[87]Zamarin D, Garcia-Sastre A, Xiao X, et al. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog.2005,1(1):e4.
[88]Conenello GM, Tisoncik JR, Rosenzweig E, et al. A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo. J Virol.2011,85(2):652-62.
[89]Conenello GM, Zamarin D, Perrone LA, et al. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog.2007,3(10):1414-21.
[90]Seo SH, Hoffmann E, Webster RG Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med.2002,8(9):950-4.
[91]Dankar SK, Wang S, Ping J, et al. Influenza A virus NS1 gene mutations F103L and M106I increase replication arid virulence. Virol J.2011,8:13.
[92]Stiver G The treatment of influenza with antiviral drugs.CMAJ.2001,45(12): 3403-8.
[93]Zaraket H, Saito R, Suzuki Y,et al. Genetic makeup of amantadine- resistant and oseltamivir-resistant human influenza A/H1N1 viruses. J Clin Microbiol.2010,48 (4):1085-92.
[94]Le QM, Kiso M, Someya K, et al. Avian flu:isolation of drug-resistant H5N1 virus. Nature.2005,437(7062):1108.
[95]Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997,388(6640):394-7.
[96]Barton GM, Medzhitov R. Toll-like receptors and their ligands. Curr Top Microbiol Immunol.2002,270:81-92.
[97]Sloane JA, Blitz D, Margolin Z, et al. A clear and present danger:endogenous ligands of Toll-like receptors. Neuromolecular Med.2010,12(2):149-63.
[98]Hopkins PA, Sriskandan S. Mammalian Toll-like receptors:to immunity and beyond. Clin Exp Immunol.2005,140(3):395-407.
[99]Xie XH, Law HK, Wang LJ, et al. Lipopolysaccharide induces IL-6 production in respiratory syncytial virus-infected airway epithelial cells through the toll-like receptor 4 signaling pathway. Pediatr Res.2009,65(2):156-62.
[100]Jeisy-Scott V, Davis WG, Patel JR, et al. Increased MDSC accumulation and Th2 biased response to influenza A virus infection in the absence of TLR7 in mice. PLoS One.2011,6(9):e25242.
[101]Deng G, Bi J, Kong F, et al. Acute respiratory distress syndrome induced by H9N2 virus in mice. Arch Virol,2010,155(2):187-95.
[102]Kimura Y. Cytokines and chemokines induced by influenza virus infection. Nihon Rinsho,2006,64(10):1822-7.
[103]Chan MC, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells.Respir Res,2005,6:135.
[104]吕卫华,黄卫良.急性支气管肺炎患儿血清SOD及相关细胞因子测定的意义.放射免疫学杂志,2010,23(3)：250-3.
[105]Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science.2004,303(5663): 1529-31.
[106]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011,81(7):825-37.
[107]Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.J Virol.2005,79(11):7269-72.
[108]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors.Neuromolecular Med.2010,12(2): 149-63.
[109]Henrick BM, Nag K, Yao XD, et al. Milk matters:soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLoS One.2012,7(7):e40138.
[110]Yu WC, Chan RW, Wang J, et al. Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. J Virol.2011,85(14):6844-55.
[111]Chan MC, Chan RW, Yu WC, et al.Influenza H5N1 virus infection of polarized human alveolar epithelial cells and lung microvascular endothelial cells. Respir Res.2009,10:102.
[112]窦颖,赵晓东,赵耀.人偏肺病毒感染人肺上皮细胞后Toll样受体的表达及其功能.中华微生物学和免疫学杂志,2009,12：1122-7.
[113]黄升海,魏伟,云云.呼吸道合胞病毒感染上调Toll样受体7和3基因的早期表达.微生物学报,2009,49(2)：239-45.
[114]黄丽,郭显蓉,屠宴会,等.A549细胞和Hep-2细胞表面糖链类型鉴定及其与H5N1型禽流感病毒结合的特性.基础医学与临床,2010,12：1318-24.
[115]牛旭艳,张春晶,顾立刚.毒热平注射液对甲型流感病毒H3N2体外感染细胞中TLR7信号通路的影响.中华中医药杂志,2010,2：194-7.
[116]Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog.2006,2(6):e53.
[117]Qu B, Li X, Gao W, et al. Human intestinal epithelial cells are susceptible to influenza virus subtype H9N2.Virus Res.2012,163(1):151-9.
[1]Carty M, Bowie AG. Recent insights into the role of Toll-like receptors in viral infection. Clin Exp Immunol.2010,161(3):397-406.
[2]Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors. Neuromolecular Med.2010,12(2): 149-63.
[3]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011,81 (7):825-37.
[4]Rallabhandi P, Phillips RL, Boukhvalova MS, et al.Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. MBio.2012,3(4). pii:e00218-12.
[5]Xie XH, Law HK, Wang LJ, et al. Lipopolysaccharide induces IL-6 production in respiratory syncytial virus-infected airway epithelial cells through the toll-like receptor 4 signaling pathway. Pediatr Res.2009,65(2):156-62.
[6]Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol.2009,83(3):1492-1500.
[7]Klein Klouwenberg P, Tan L, Werkman W, et al. The role of Toll-like receptors in regulating the immune response against respiratory syncytial virus. Crit Rev Immunol.2009,29(6):531-50.
[8]Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol.2009,83(3):1492-500.
[9]Davidson S, Kaiko G, Loh Z, et al. Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway. J Immunol.2011,186(10):5938-48.
[10]van der Sluijs KF, van Elden L, Nijhuis M, et al. Toll-like receptor 4 is not involved in host defense against respiratory tract infection with Sendai virus. Immunol Lett. 2003,89(2-3):201-6.
[11]Wei XQ, Guo YW, Liu JJ, et al. The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B. Clin Invest Med.2008,31(3): E123-30.
[12]Chen Z, Cheng Y, Xu Y, et al. Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol 2008,128:400-8.
[13]Wu J, Meng Z, Jiang M, et al. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology.2010,129(3): 363-74.
[14]Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.J Virol.2005,79(11):7269-72.
[15]Abe T, Fukuhara T, Wen X, et al. CD44 participates in IP-10 induction in cells in which hepatitis C virus RNA is replicating, through an interaction with Toll-like receptor 2 and hyaluronan. J Virol.2012,86(11):6159-70.
[16]Chang S, Dolganiuc A, Szabo G. Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol.2007,82(3):479-87.
[17]Guo J, Loke J, Zheng F, et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology.2009,49(3):960-8.
[18]Macdonald A, Harris M. Hepatitis C virus NS5A:tales of a promiscuous protein. J Gen Virol.2004,85(Pt 9):2485-502.
[19]Machida K, Tsukamoto H, Mkrtchyan H, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc NatI Acad Sci USA.2009,106(5):1548-53.
[20]Sundstrom JB, Little DM, Villinger F, et al. Signaling through Toll-like receptors triggers HIV-1 replication in latently infected mast cells. J Immunol.2004,172(7):4391-401.
[21]Crane M, Visvanathan K, Lewin SR. HIV Infection and TLR Signalling in the Liver. Gastroenterol Res Pract.2012,2012:473925.
[22]Pine SO, McElrath MJ, Bochud PY. Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS.2009,23(18):2387-95.
[23]Rassa JC, Meyers JL, Zhang Y, et al. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA.2002,99(4):2281-6.
[24]Lagos D, Vart RJ, Gratrix F, et al. Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe.2008,4(5):470-83.
[25]Ahmad H, Gubbels R, Ehlers E, et al. Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). J Biol Chem.2011,286(10):7865-72.
[26]Li H, Li X, Wei Y, et al. HSV-2 induces TLRs and NF-kappaB-dependent cytokines in cervical epithelial cells.Biochem Biophys Res Commun.2009,379(3): 686-90.
[27]S(?)rensen LN, Reinert LS, Malmgaard L, et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol.2008,181(12): 8604-12.
[28]Fairweather D, Yusung S, Frisancho S, et al. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol.2003,170(9):4731-7.
[29]Triantafilou K, Triantafilou M. Coxsackievirus B4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4. J Virol.2004,78(20): 11313-20.
[30]Zhu J, Martinez J, Huang X, Yang Y. Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta. Blood.2007,109(2):619-25.
[31]Martinez J, Huang X, Yang Y. Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection. PLoS Pathog. 2010,6(3):e1000811.
[32]Hutchens MA, Luker KE, Sonstein J, et al. Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection. PLoS Pathog.2008,4(9):e1000153.
[33]Samuelsson C, Hausmann J, Lauterbach H, et al. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. J Clin Invest.2008,118(5):1776-84.
[34]Georgel P, Jiang Z, Kunz S, et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology. 2007,362(2):304-13.
[35]Schabbauer G, Luyendyk J, Crozat K, et al. TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages. Mol Immunol.2008,45(10):2790-6.
[36]Yokota S, Okabayashi T, Yokosawa N, Fujii N. Measles virus P protein suppresses Toll-like receptor signal through up-regulation of ubiquitin-modifying enzyme A20. FASEB J.2008,22(1):74-83.
[37]Ovsyannikova IG, Haralambieva IH, Vierkant RA, et al. The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity. Hum Genet.2011,130(4):547-61.
[38]Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A,2007, 104(30):12479-81.
[39]Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science.2004,303(5663): 1529-31.
[40]Ramos I, Fernandez-Sesma A. Cell receptors for influenza a viruses and the innate immune response. Front Microbiol.2012,3:117.
[41]Jeisy-Scott V, Davis WG, Patel JR, et al. Increased MDSC accumulation and Th2 biased response to influenza A virus infection in the absence of TLR7 in mice. PLoS One.2011,6(9):e25242.
[42]Maschalidi S, Hassler S, Blanc F, et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog. 2012;8(8):e1002841.
[43]Karnam G, Rygiel TP, Raaben M, et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS Pathog.2012,8(5):e1002710.
[44]Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog.2006,2(6):e53.
[45]Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell.2008,133(2): 235-49.
[46]Nang NT, Lee JS, Song BM, et al. Induction of inflammatory cytokines and toll-like receptors in chickens infected with avian H9N2 influenza virus. Vet Res.2011,42(1):64.
[47]Hayashi T, Hiromoto Y, Chaichoune K, et al. Host cytokine responses of pigeons infected with highly pathogenic Thai avian influenza viruses of subtype H5N1 isolated from wild birds. PLoS One.2011,6(8):e23103.
[48]Zhou S, Halle A, Kurt-Jones EA, et al. Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses. J Neuroimmunol.2008,194(1-2):70-82.
[49]Gaudreault E, Fiola S, Olivier M, Gosselin J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J Virol.2007,81(15):8016-24.
[50]Lai Y, Yi G, Chen A, et al. Viral double-strand RNA-binding proteins can enhance innate immune signaling by toll-like Receptor 3. PLoS One.2011,6(10):e25837.
[51]Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med.2004,10(12): 1366-73.
[52]Pott J, Stockinger S, Torow N, et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 2012,8(5):e1002670.
[53]Kindberg E, Vene S, Mickiene A, et al. A functional Toll-like receptor 3 gene (TLR3) may be a risk factor for tick-borne encephalitis virus (TBEV) infection. J Infect Dis.2011,203(4):523-8.
[54]Wang Q, Miller DJ, Bowman ER, et al. MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness. PLoS Pathog.2011,7(5):e1002070.
[55]Browne EP. Toll-like receptor 7 controls the anti-retroviral germinal center response. PLoS Pathog.2011,7(10):e1002293.
[56]Henrick BM, Nag K, Yao XD, et al. Milk matters:soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLoS One.2012,7(7):e40138.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |