福建省狂犬病流行病学及病毒学特征研究
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摘要
目的
近些年,我国人间狂犬病报告病例数呈递增态势,狂犬病已成为当前重大的公共卫生问题。我国关于狂犬病流行病学、病原学的深入研究较少,整体资料不全,福建省这方面的研究更是薄弱,尚不清楚我省狂犬病毒主要宿主的病毒携带情况和免疫情况,不清楚居民对狂犬病的认知程度及养犬情况等;国内狂犬病毒街毒株的分离报道较少,尚未见在福建省境内分离出狂犬病毒的报道,对福建省境内狂犬病毒的流行毒株及其特征尚不清楚。因此,为了更好地预防和控制狂犬病,非常有必要开展系统的狂犬病流行病学研究,获得狂犬病流行现状的基础资料,了解影响狂犬病发病率的主要因素;也很有必要进行狂犬病毒流行毒株的分离鉴定、病原生物学和遗传学特征的研究。因养犬数的增加导致犬伤患者也不断增加,推进和提高犬伤患者免疫后血清抗体及犬唾液带毒的检测方法也迫在眉捷。
方法
1、针对狂犬病高发的实际情况,通过系统的流行病学调查研究,以获得狂犬病流行现状的基础资料;从生态学角度收集影响狂犬病发病率有关因素的资料,通过负二项回归模型筛查出影响狂犬病发病率的主要因素。
2、运用MIT和CIT法从疑似狂犬的脑组织中进行狂犬病毒街毒株的分离与鉴定,采取分段RT-PCR的方法,对所分离的街毒株进行序列扩增、克隆、测序,拼接获得全基因组序列,并运用生物学软件对基因组结构进行分析与比较;
3、通过收集福建省不同时间、不同地区的犬脑组织,进行实验室检测诊断,对阳性标本进行N基因全长的扩增、克隆和测序,结合疫情资料进行狂犬病的分子流行病学研究。
4、选取CTN株狂犬病毒糖蛋白富集表位基因片段进行克隆、表达和纯化,人工获得狂犬病毒糖蛋白抗原,为探索犬伤患者免疫后血清抗体及犬唾液带毒检测方法的提高奠定基础。
结果
1、从2000～2006年福建省每年均有人间狂犬病疫情发生,平均发病率为0.07/10万。2002~2006年福建省人狂犬病报告病例,各地分布不一,夏秋季节发病相对较多,病例主要集中在30~60岁之间,男性多于女性,农民发病人数最多。
2、福建省3个调查地区的平均家庭养犬率约为46.67%,人均养犬数约为0.13只,每家养犬数约为0.63只。家犬平均免疫率为5.54%。
3、福建省普通群众对狂犬病的认知情况较差,狂犬病专业技术人员,总体对狂犬病犬伤情况处理的知识水平较高。
4、研究认为狂犬病的发病率与犬的免疫率及普通群众狂犬病知识认知能力有关。犬免疫率每增加1%,5年累积发病率为原来的79%即下降了21%。普通群众狂犬病知识认知能力平均每增加0.1分,5年累积发病率为原来的80%即下降了20%。
5、本研究通过RT-nested-PCR法从表观健康犬脑组织中检测出狂犬病毒,并经基因测序证实表观健康犬携带狂犬病毒,为狂犬病的预防和控制提供了有力的实验证据。
6、首次在福建省成功分离出狂犬病毒街毒株(7株),并完成其中两株(FJ008、FJ009)的生物学特性和全基因组序列测定。
7、从福建省各地收集的犬脑组织标本共89份,通过RT-nested-PCR扩增、纯化、克隆,获得19条包含N基因完整读码框的序列。根据核苷酸和推导的氨基酸的同源性高低,把19份含有RABV RNA的标本分为三个群组,a群组包括:FJ001、FJ002、FJ003、FJ012、FJ013、FJ014;b群组包括: FJ008、FJ009、FJ010、FJ011、FJ015、FJ016、FJ017、FJ018、FJ019;c群组包括: FJ004、FJ005、FJ005、FJ007。各群组内部RABV N基因的核苷酸同源性在99.70~100%之间,群组间RABV N基因的核苷酸同源性在86.43~89.28%,各群组内部RABV N基因的氨基酸同源性在98.86~100%之间,群组间RABV N基因的氨基酸同源性在95.33~98.44%。结合标本来源地,证实福建省狂犬病具有显著的地域分布特征。
8、福建省狂犬病的流行毒株与目前常用的各种疫苗株N基因序列比对同源性在86.47~98.89%之间,均属于基因I型,提示目前使用的疫苗能较好地保护福建省RABV流行毒株的感染。
9、完成了重组质粒pHTb-624的高效表达和纯化,获得一批高纯度的狂犬病毒糖蛋白重组抗原,应用于犬伤患者免疫后血清抗体的检测,与市场上主流试剂盒检测结果没有明显差异,提示该重组抗原具有较好的应用价值。
结论
1、福建省近些年狂犬病高发,居民养犬众多,犬免疫率低下,普通群众狂犬病相关知识薄弱。犬免疫率低下及普通群众狂犬病相关知识薄弱是福建省狂犬病高发的主要影响因素。
2、首次在福建省成功分离出7株狂犬病毒街毒株,并完成其中两株街毒株(FJ008、FJ009)的生物学特性和全基因组序列测定。
3、完成福建省狂犬病毒流行毒株的基因分型和分子流行病学研究。证实福建省存在表观健康犬携带狂犬病毒的现象,为狂犬病的预防和控制提供了有力证据。虽然福建省狂犬病具有显著的地域分布特征,本研究发现福建省狂犬病的流行毒株与目前使用的各种疫苗株N基因序列比对同源性在86.47~98.89%之间,均属于基因I型,目前使用的疫苗还是可以较好地保护福建省流行毒株的感染。
4、完成了重组质粒pHTb-624的高效表达和纯化,获得一批高纯度的狂犬病毒糖蛋白重组抗原,应用于犬伤患者免疫后血清抗体的检测与市场上主流试剂盒检测结果没有明显差异,提示该重组抗原具有较好的应用价值。
Objective
In recent years, the number of reported human rabies cases has been increasing so rapidly that rabies has become a serious public health problem in China. General information for epidemiology of nation-wide rabies, in-depth study of rabies isolates around China were incomplete. In Fujian, particularly, research in this area is rare. The main host of rabies virus in Fujian and immune situation is not clear, nor does the residents’knowledge and awareness of rabies. So far no domestic rabies virus street strains has been isolated in Fujian yet the characteristics of prevalent street strains in Fujian remains unkown. Therefore, in order to enhance prevention and control of rabies, it is necessary to systematically investigate the epidemiology of rabies, obtain detailed data of rabies prevalence, and to understand the main impact factors on rabies incidence in Fujian. Meanwhile, it is urgent to isolate rabies virus street strains, study the virological characteristics of the isolates. Additionally, the increasing number of kennel dogs is resulting with raised number of trauma patients, hence, it is also necessary to develop rapid sera antibody detection for injured patients and viral antigen detection of saliva specimens from possible rabid dogs.
Methods
1. A systematic epidemiological investigation was conducted to obtain basic information of rabies prevalence in Fujian. Criteria of potential ecologocal factors associated with incidence of rabies were collected and analyzed with the negative binomial regression model.
2. Street trains were isolated from brain of suspected rabid dogs, via mouse inoculation technique(MIT) and cell culture inoculation technique(CIT). Complete genome sequences were obtained by RT-PCR, cloning and sequencing, the genomic structure was analyzed and compared.
3. Dozens of canine brains were collected from several districts of Fujian in the past 3 years. Full-length N genes from all positive specimens were amplified, cloned and sequenced.
4. Epitope of viral glycoprotein from the CTN strain was cloned,expressed and purified, a recombinant viral glycoprotein antigen was obtained.
Results:
1. From 2000 to 2006, human rabies cases were reported in Fujian with an average incidence rate of 0.07/100,000. These cases were unevenly distributed in several districts of Fujian, most of the cases clustered in the summer and autumn, aged from 30-60, more male victims than female, peasants are more likely to be rabies victims.
2. In average, 46.67% of homes from 3 districts investigated in Fujian has dogs, 0.13 dogs per capita, 0.63 dogs per residency. The mean immunization rate was 5.54%.
3. Although general awareness of rabies was poor for public in Fujian, satisfactory results were obtained from professional staff treating rabid bites.
4. Our data revealed that the incidence of rabies was associated with dog immunization rates and general knowledge of rabies from the public. 1% increase of canine immunization rate would result dramatic drop of 5-year cumulative incidence rate from 79% to 21%. 0.1 points increase of knowledge in the public would result decrease of 5-year cumulative incidence rate from 80% to 20%.
5. In this study, fragments were amplified from brains of healthy dogs by RT-nested-PCR. Sequence analyses confirmed their rabid origin, indicating healthy dogs may act as hosts for rabies viruses. These results provided solid laboratory evidence for rabies prevention and control.
6. Seven street strains were successfully isolated, biological features were studied and complete genome sequences were obtained in two strains(FJ008, FJ009)
7. Nineteen full-length N genes were amplified from 89 canine brains collected from several districts. Based on nucleotide and deduced amino acid homology level, these 19 RABV fragments were classified into three groups, FJ001, FJ002, FJ003, FJ012, FJ013 and FJ014 belonged to group A; FJ008, FJ009, FJ010, FJ011, FJ015, FJ016, FJ017, FJ018 and FJ019 belonged to group B; FJ004, FJ005, FJ005 and FJ007 belonged to group C. The nucleotide homology of RABV N gene was between 99.70 ~ 100% within the group, 86.43 ~ 89.28% at inter-group level. The amino acid homology of RABV N gene ranged 98.86 ~ 100%, while 95.33 ~ 98.44% at inter-group level. These results suggested distinct geographic distribution of rabies viruses in Fujian.
8 .Comparison of N gene sequences from the prevalent street strains in Fujian with those from 4 commercial rabies vaccines revealed a homology between 86.47 ~ 98.89%, all belonged to Genotype I, suggesting that current vaccines could effectively protect individuals from RABV infection in Fujian.
9. A recombinant plasmid pHTb-624's was constructed, confirmed with high-level expression and purification. This high-purity recombinant viral glycoprotein antigen was used in serum antibody detection for post-exposure patients, no significant difference was observed with current commercial kits.
Conclusion
1. The high incidence of rabies in Fujian in recent years was caused by excessive dogs in the community, low immunization rates in dogs, relatively unawareness of rabies in the public. Low immunization rates in dogs and weakness of the knowledge on rabies in the public were the main factors for high incidence of rabies in Fujian..
2. This was the first reports that seven street strains were successfully isolated, biological features were studied and complete genome sequences were obtained in two strains(FJ008, FJ009)
3. Genotyping of 19 viral fragments amplified from canine brains. Our data demonstrated that healthy dogs could be rabies hosts, These results provided solid laboratory evidence for rabies prevention and control in Fujian. Although distinct geographic distribution of rabies viruses were observed in Fujian, comparison of N gene sequences from the prevalent street strains in Fujian with those from 4 commercial rabies vaccines revealed a homology between 86.47 ~ 98.89%, all belonged to Genotype I, current vaccines could effectively protect individuals from RABV infection in Fujian.
4. A recombinant plasmid pHTb-624's was constructed, confirmed with high-level expression and purification. This high-purity recombinant viral glycoprotein antigen was used in serum antibody detection for post-exposure patients, no significant difference was observed with current commercial kits.
近些年,我国人间狂犬病报告病例数呈递增态势,狂犬病已成为当前重大的公共卫生问题。我国关于狂犬病流行病学、病原学的深入研究较少,整体资料不全,福建省这方面的研究更是薄弱,尚不清楚我省狂犬病毒主要宿主的病毒携带情况和免疫情况,不清楚居民对狂犬病的认知程度及养犬情况等;国内狂犬病毒街毒株的分离报道较少,尚未见在福建省境内分离出狂犬病毒的报道,对福建省境内狂犬病毒的流行毒株及其特征尚不清楚。因此,为了更好地预防和控制狂犬病,非常有必要开展系统的狂犬病流行病学研究,获得狂犬病流行现状的基础资料,了解影响狂犬病发病率的主要因素;也很有必要进行狂犬病毒流行毒株的分离鉴定、病原生物学和遗传学特征的研究。因养犬数的增加导致犬伤患者也不断增加,推进和提高犬伤患者免疫后血清抗体及犬唾液带毒的检测方法也迫在眉捷。
方法
1、针对狂犬病高发的实际情况,通过系统的流行病学调查研究,以获得狂犬病流行现状的基础资料;从生态学角度收集影响狂犬病发病率有关因素的资料,通过负二项回归模型筛查出影响狂犬病发病率的主要因素。
2、运用MIT和CIT法从疑似狂犬的脑组织中进行狂犬病毒街毒株的分离与鉴定,采取分段RT-PCR的方法,对所分离的街毒株进行序列扩增、克隆、测序,拼接获得全基因组序列,并运用生物学软件对基因组结构进行分析与比较;
3、通过收集福建省不同时间、不同地区的犬脑组织,进行实验室检测诊断,对阳性标本进行N基因全长的扩增、克隆和测序,结合疫情资料进行狂犬病的分子流行病学研究。
4、选取CTN株狂犬病毒糖蛋白富集表位基因片段进行克隆、表达和纯化,人工获得狂犬病毒糖蛋白抗原,为探索犬伤患者免疫后血清抗体及犬唾液带毒检测方法的提高奠定基础。
结果
1、从2000～2006年福建省每年均有人间狂犬病疫情发生,平均发病率为0.07/10万。2002~2006年福建省人狂犬病报告病例,各地分布不一,夏秋季节发病相对较多,病例主要集中在30~60岁之间,男性多于女性,农民发病人数最多。
2、福建省3个调查地区的平均家庭养犬率约为46.67%,人均养犬数约为0.13只,每家养犬数约为0.63只。家犬平均免疫率为5.54%。
3、福建省普通群众对狂犬病的认知情况较差,狂犬病专业技术人员,总体对狂犬病犬伤情况处理的知识水平较高。
4、研究认为狂犬病的发病率与犬的免疫率及普通群众狂犬病知识认知能力有关。犬免疫率每增加1%,5年累积发病率为原来的79%即下降了21%。普通群众狂犬病知识认知能力平均每增加0.1分,5年累积发病率为原来的80%即下降了20%。
5、本研究通过RT-nested-PCR法从表观健康犬脑组织中检测出狂犬病毒,并经基因测序证实表观健康犬携带狂犬病毒,为狂犬病的预防和控制提供了有力的实验证据。
6、首次在福建省成功分离出狂犬病毒街毒株(7株),并完成其中两株(FJ008、FJ009)的生物学特性和全基因组序列测定。
7、从福建省各地收集的犬脑组织标本共89份,通过RT-nested-PCR扩增、纯化、克隆,获得19条包含N基因完整读码框的序列。根据核苷酸和推导的氨基酸的同源性高低,把19份含有RABV RNA的标本分为三个群组,a群组包括:FJ001、FJ002、FJ003、FJ012、FJ013、FJ014;b群组包括: FJ008、FJ009、FJ010、FJ011、FJ015、FJ016、FJ017、FJ018、FJ019;c群组包括: FJ004、FJ005、FJ005、FJ007。各群组内部RABV N基因的核苷酸同源性在99.70~100%之间,群组间RABV N基因的核苷酸同源性在86.43~89.28%,各群组内部RABV N基因的氨基酸同源性在98.86~100%之间,群组间RABV N基因的氨基酸同源性在95.33~98.44%。结合标本来源地,证实福建省狂犬病具有显著的地域分布特征。
8、福建省狂犬病的流行毒株与目前常用的各种疫苗株N基因序列比对同源性在86.47~98.89%之间,均属于基因I型,提示目前使用的疫苗能较好地保护福建省RABV流行毒株的感染。
9、完成了重组质粒pHTb-624的高效表达和纯化,获得一批高纯度的狂犬病毒糖蛋白重组抗原,应用于犬伤患者免疫后血清抗体的检测,与市场上主流试剂盒检测结果没有明显差异,提示该重组抗原具有较好的应用价值。
结论
1、福建省近些年狂犬病高发,居民养犬众多,犬免疫率低下,普通群众狂犬病相关知识薄弱。犬免疫率低下及普通群众狂犬病相关知识薄弱是福建省狂犬病高发的主要影响因素。
2、首次在福建省成功分离出7株狂犬病毒街毒株,并完成其中两株街毒株(FJ008、FJ009)的生物学特性和全基因组序列测定。
3、完成福建省狂犬病毒流行毒株的基因分型和分子流行病学研究。证实福建省存在表观健康犬携带狂犬病毒的现象,为狂犬病的预防和控制提供了有力证据。虽然福建省狂犬病具有显著的地域分布特征,本研究发现福建省狂犬病的流行毒株与目前使用的各种疫苗株N基因序列比对同源性在86.47~98.89%之间,均属于基因I型,目前使用的疫苗还是可以较好地保护福建省流行毒株的感染。
4、完成了重组质粒pHTb-624的高效表达和纯化,获得一批高纯度的狂犬病毒糖蛋白重组抗原,应用于犬伤患者免疫后血清抗体的检测与市场上主流试剂盒检测结果没有明显差异,提示该重组抗原具有较好的应用价值。
Objective
In recent years, the number of reported human rabies cases has been increasing so rapidly that rabies has become a serious public health problem in China. General information for epidemiology of nation-wide rabies, in-depth study of rabies isolates around China were incomplete. In Fujian, particularly, research in this area is rare. The main host of rabies virus in Fujian and immune situation is not clear, nor does the residents’knowledge and awareness of rabies. So far no domestic rabies virus street strains has been isolated in Fujian yet the characteristics of prevalent street strains in Fujian remains unkown. Therefore, in order to enhance prevention and control of rabies, it is necessary to systematically investigate the epidemiology of rabies, obtain detailed data of rabies prevalence, and to understand the main impact factors on rabies incidence in Fujian. Meanwhile, it is urgent to isolate rabies virus street strains, study the virological characteristics of the isolates. Additionally, the increasing number of kennel dogs is resulting with raised number of trauma patients, hence, it is also necessary to develop rapid sera antibody detection for injured patients and viral antigen detection of saliva specimens from possible rabid dogs.
Methods
1. A systematic epidemiological investigation was conducted to obtain basic information of rabies prevalence in Fujian. Criteria of potential ecologocal factors associated with incidence of rabies were collected and analyzed with the negative binomial regression model.
2. Street trains were isolated from brain of suspected rabid dogs, via mouse inoculation technique(MIT) and cell culture inoculation technique(CIT). Complete genome sequences were obtained by RT-PCR, cloning and sequencing, the genomic structure was analyzed and compared.
3. Dozens of canine brains were collected from several districts of Fujian in the past 3 years. Full-length N genes from all positive specimens were amplified, cloned and sequenced.
4. Epitope of viral glycoprotein from the CTN strain was cloned,expressed and purified, a recombinant viral glycoprotein antigen was obtained.
Results:
1. From 2000 to 2006, human rabies cases were reported in Fujian with an average incidence rate of 0.07/100,000. These cases were unevenly distributed in several districts of Fujian, most of the cases clustered in the summer and autumn, aged from 30-60, more male victims than female, peasants are more likely to be rabies victims.
2. In average, 46.67% of homes from 3 districts investigated in Fujian has dogs, 0.13 dogs per capita, 0.63 dogs per residency. The mean immunization rate was 5.54%.
3. Although general awareness of rabies was poor for public in Fujian, satisfactory results were obtained from professional staff treating rabid bites.
4. Our data revealed that the incidence of rabies was associated with dog immunization rates and general knowledge of rabies from the public. 1% increase of canine immunization rate would result dramatic drop of 5-year cumulative incidence rate from 79% to 21%. 0.1 points increase of knowledge in the public would result decrease of 5-year cumulative incidence rate from 80% to 20%.
5. In this study, fragments were amplified from brains of healthy dogs by RT-nested-PCR. Sequence analyses confirmed their rabid origin, indicating healthy dogs may act as hosts for rabies viruses. These results provided solid laboratory evidence for rabies prevention and control.
6. Seven street strains were successfully isolated, biological features were studied and complete genome sequences were obtained in two strains(FJ008, FJ009)
7. Nineteen full-length N genes were amplified from 89 canine brains collected from several districts. Based on nucleotide and deduced amino acid homology level, these 19 RABV fragments were classified into three groups, FJ001, FJ002, FJ003, FJ012, FJ013 and FJ014 belonged to group A; FJ008, FJ009, FJ010, FJ011, FJ015, FJ016, FJ017, FJ018 and FJ019 belonged to group B; FJ004, FJ005, FJ005 and FJ007 belonged to group C. The nucleotide homology of RABV N gene was between 99.70 ~ 100% within the group, 86.43 ~ 89.28% at inter-group level. The amino acid homology of RABV N gene ranged 98.86 ~ 100%, while 95.33 ~ 98.44% at inter-group level. These results suggested distinct geographic distribution of rabies viruses in Fujian.
8 .Comparison of N gene sequences from the prevalent street strains in Fujian with those from 4 commercial rabies vaccines revealed a homology between 86.47 ~ 98.89%, all belonged to Genotype I, suggesting that current vaccines could effectively protect individuals from RABV infection in Fujian.
9. A recombinant plasmid pHTb-624's was constructed, confirmed with high-level expression and purification. This high-purity recombinant viral glycoprotein antigen was used in serum antibody detection for post-exposure patients, no significant difference was observed with current commercial kits.
Conclusion
1. The high incidence of rabies in Fujian in recent years was caused by excessive dogs in the community, low immunization rates in dogs, relatively unawareness of rabies in the public. Low immunization rates in dogs and weakness of the knowledge on rabies in the public were the main factors for high incidence of rabies in Fujian..
2. This was the first reports that seven street strains were successfully isolated, biological features were studied and complete genome sequences were obtained in two strains(FJ008, FJ009)
3. Genotyping of 19 viral fragments amplified from canine brains. Our data demonstrated that healthy dogs could be rabies hosts, These results provided solid laboratory evidence for rabies prevention and control in Fujian. Although distinct geographic distribution of rabies viruses were observed in Fujian, comparison of N gene sequences from the prevalent street strains in Fujian with those from 4 commercial rabies vaccines revealed a homology between 86.47 ~ 98.89%, all belonged to Genotype I, current vaccines could effectively protect individuals from RABV infection in Fujian.
4. A recombinant plasmid pHTb-624's was constructed, confirmed with high-level expression and purification. This high-purity recombinant viral glycoprotein antigen was used in serum antibody detection for post-exposure patients, no significant difference was observed with current commercial kits.
引文
[1]唐家琪.自然疫源性疾病[M].北京:科学出版社,2005:358.
[2]王显军,李忠,王萍等.山东省农村地区21例狂犬病患者流行病学调查[J].中华流行病学杂志,2005;26(7):477.
[3]郭绶衡,唐青,李浩等.中国31省1991-2005年狂犬病流行情况比较分析[J].中华流行病学杂志,2007;28(4):374-376.
[4]梁海荣,唐焕文,李华文等. 2463例狂犬病疫苗免疫后抗体水平及其影响因素分析[J].中国人兽共患病杂志,2003;19(6):118.
[5]徐伏牛,任军,许明德等.流行病学调查表备览[M].安徽:科学技术出版社,2004:61-67.
[6]Laiskonis A, Bareisiene MV, Velyvyte D, et al. Surveillance of animal and human rabies in Lithuania from 1991 to 2001[J]. Med Mal Infect,2006,36(1):4-8.
[7]谢世宏,史秀山,王显军等.狂犬病防治手册[M].四川:科学技术出版社,2003:15~40,219-225.
[8]Bocsan IS,Brumboiu I, Coman A,et al. Rabies surveillance in the rural population of Cluj County,Romania[J].Rural Remote Health,2005,5(3):431.
[9]World Health Organization Department of Communicable Disease Surveillanceand Response. Strategies for the control and eliminationof rabies in Asia.Geneva:The Organization,2001.
[10]Conzelmann KK,Cox JH,Schneider LG,et al. Molecular cloning and complete nucleotide sequence of the attenuated rabies virus SAD B19. Vriology. 1990,175(2):485-99
[11]徐葛林,Li Ku,吴杰等.中国19个狂犬病毒街离分离株N基因的序列分析[J].病毒学报,2002;18(1):48-51.
[12]Picard Meyer E , Bruyere V , Barrat J ,et al. Development of a hemi-nested RT-PCR method for the specific determination of European Bat Lyssavirus 1[J ] . Comparison with other rabies diagnostic methods. Vaccine ,2004,22 (15– 16):921 -1929.
[13]Meslin FX.Kaplan MM.Koprowski H.Laboratory techniquesin rabies[M].Fourthedition,WTO,Geneva.1996,88-95
[14]Badrane H,Bahloul C,Perrin P,et al.Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity.Virol.2001,27:3268-3276
[15]Qi Liu,Yi Xiong,Ting Rong Luo,et al. Molecular epidemiology of rabies in Guangxi Province, south of China. [J]Journal of Clinical Virology,2007,39 (4):295-303.
[16]S. Vázquez-Morón,A. Avellón, J.E. Echevarría. RT-PCR for detection of all seven genotypes of Lyssavirus genus. [J]Journal of Virological Method,2006,135 (2):281-287.
[17] Ajayi Bb,Rabo JS,Baba SS. Rabies in apparently healthy dogs:histological and immunohistochemical studies[J]. Niger Postgrad Med J,2006,13(2):128-134.
[18]ErmineA.1.arzulD,Guesdon J I, et al. PCR amplification of rabies virus nucleic acids from toialnlousebrainRNA.MoleeulCellulProb.1990.4:189- 191.
[19]SaeralnentoD.PCRteehniqueasanaltemativemethod fordiagiagnosis and molecular pidemio]ogy of rabies virus. Moleeul Celhd Prolz.1991.5:229-240.
[20]KamolvarinN.Tirawatnpong T.RatlanasiwamokeR,etal.Diagnosis of rabies by polymerase Chainreaction with nested primers.J lnf Dis, 1993.167:207-210.
[21]罗廷荣,源宣之等,NestedPCR检测狂犬病毒方法的建立及病毒在小鼠体内的多行动态,中国兽医学报,2000,20(6),535-538.
[22]Tordo N,Poch O,Ermine A,et al. Completion of the rabies virus genome sequence determination:highly conserved domains among the L(polymerase)proteins of unsegmented negative-strand RNA viruses. [J]. Virology. 1988,165(2):565-76.
[23]W illiam H W unner, Jovi K L arson, Bernhard D ietzschold,et al. The molecular biology of rabies viruses. [J].Review s of infectious diseases,1988,Vo l. 10,Supplement 4:S771- S784
[24]杨淑君.北京又增10万条狗. [2007-08-07].http://www.bj.xinhuanet.com/bjfs/2007-08/07/content_10792158.htm
[25] Yelverton E, Norton S, Obijeski JF, et al.Rabies virus glycoprotein analogs: biosynthesis in Escherichia coli[J]. Science,1983,219(4585):614-20.
[26] Klepfer SR, Debouck C, Uffelman J, et al.Characterization of rabies glycoproteinexpressed in yeast[J]. Arch Virol,1993:128(3-4):269-86.
[27] Yokomizo AY, Jorge SA, Astray RM, et al. Rabies virus glycoprotein expression in Drosophila S2 cells. I. Functional recombinant protein in stable co-transfected cell line.[J]. Biotechnol J,2007,2(1):102-109.
[28] Hu R, Zhang S, Fooks AR, et al. Prevention of rabies virus infection in dogs by a recombinant canine adenovirus type-2 encoding the rabies rirus glycoprotein[J]. Microbes Infec,2006,8(4):1090-1097.
[29]Prehaud C,Coulon P,LaFay F,et al. Antigenic site II of the rabies virus glycoprotein:structrue and role in viral virulence[J]. J Virol,1988,62(1):1
[30]Delwart E L, E G Shpaer, J I Mullins, et al. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes[J].Science ,1993,262:1257-1261.
[1]唐家琪.自然疫源性疾病[M].北京：科学出版社，2005：358.
[2]World Health Organization Department of Communicable Disease Surveillanceand Response.Strategies for the control and eliminationof rabies in Asia.Geneva:The Organization,2001.
[3] Tang XC,Luo M,Zhang SY,et al.Pivotal role of dogs in rabiestransmission,China.Emerging Infectious Diseases,2005,1 1(12): 1970-1972.
[4]俞永新主编，狂犬病和狂犬病疫苗，中国医药科技出版社，2001
[5]KawaiA,AnzaiJ,HondaY,et al.Monoclonal antibody recognizes the phosphatase-sensitive epitope of rabies virus nucleoprotein.MicrobiolImmunol. 1997,41(1):33-42
[6]Raux H,Flamand A,Blondel D.Interaction of the rabies virus P protein with theLC8 dynein light chain.Journal of Virology.2000,74(21): 10212-6.
[7]Mebatsion T,Weiland F,Conzelmann KK.Matrix protein of rabies virus isresponsible for the assembly and budding of bullet-shaped particles and interacts withthe transmembrane spike glycoprotein G. Journal of Virology. 1999,73(1):242-50.
[8]Harty RN,Paragas 1,Sudol M.Palese P A proline-rich motif within the matrixprotein ofvesicular stomatitis virus and rabies virus interacts with WW domains ofcellular proteins:implications for viral budding. Journal of Virology. 1999,73(4):2921-9
[9]Schoehm G,Iseni F,Mavrakis M,Blondel D,Ruigrok R W.Sreucture of recombinantrabies virus nucleoprotein-RNA complex and identification of the phosphoproteinbinding site.Virol,2001,75(1):490-498.
[10]Ashim K.Gupta,Danielle Blondel,Suresh Choudhary,Amiya K Banerjee.ThePhosphoprotein of Rabies Virus Is Phosphoprotein by a Unique Cellular ProteinKinase and Specific Isomers of Protein Kinase C. Journal of Virology.2000, 1:91-98.
[11]Harty R N,Paragas J,Sudol M,Palese P.A praline-rich motif within matrix proteinof vescular stomatitis virus and rabies virus interacts with WW domains of cellularproteins:implication for viral budding. Virol, 1999,73(4):2921-2929.
[12]Mebatsion T,Weiland F,Conzelmann K.Matrix protein of rabies virus isresponsible for the assembly and budding of bullet-shaped particles and interacts withthe transmembrane spike glycoprotein G.Virol, 1999,73(1):242-250.
[13]Morimoto K,Foley HD,McGettigan JP,Schnell MJ,Dietzschold B. Reinvestigationof the role of the rabies virus glycoprotein in viral pathogenesis using a reversegenetics apptoach.Neurovirol.2000,6(5):373-381.
[14]金奇主编.医学分子病毒学.北京：科学出版社，2001，381~390.
[15]Bunschoten H,Gore M,Claassen IJ,et al.Characterization of a newvirus-neutralizing epitope that denotes a sequential determinant on the rabies virusglycoprotein.Journal of General Virology. 1989,70(2):291-8.
[16]Dietzschold M,gore M,MarchadierD et al. Structural and immunologicalcharcterization of a linear virus neutralizing epitope of the rabies virus glycoproteinand its possible use in a synthetic vaccine.Journal of Virology. 1990, 64:3804.
[17]van der Heijden RW,Langedijk JP,Groen J,et al.Structural and functional studieson a unique linear neutralizing antigenic site(G5)of the rabies virus glycoproteinJournal of General Virology.1993,74(8):1539-45.
[18]Macfarlan RI,Dietzschold B,Wiktor TJ,et al.T cell responses to cleaved rabiesvirus glycoprotein and to synthetic peptides.Journal of immunology. 1984,133(5):2748-52.
[19]Morimoto K,Foley HD,McGettigan JP,et al.Reinvestigation of therole of therabies virus glycoprotein in viral pathogenesis using a reverse genetics approach.Journal of neurovirology.2000,6(5):373-81.
[20]Schnell MJ,Conzelmann KK.Polymerase activity of in vitro mutated rabies virusLprotein.Virology.1995,20;214(2):522-30.
[21]Morimoto K,Ni YJ,Kawai A.Syncytium formation is induced in the murineneuroblastoma cell cultures which produce pathogenic type G proteins of the rabiesvirus.Virology.1992,189(1):203-16.
[22]Le Mercier P,Jacob Y,Tordo N.The complete Mokola virus genome sequence:structureof the RNA-dependent RNA polymerase.Journal of General Virology.1997,78(7):1571-1576.
[23] Elizabeth R,Conzelmann KK,FadaiGhotbi B,et al.Spread and pathogenic haracteristics of a G-deficient rabies virus recombinant:an in vitroand in vivo study. Journal of General Virology.2000,8I(9):2147-53.
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[2]王显军,李忠,王萍等.山东省农村地区21例狂犬病患者流行病学调查[J].中华流行病学杂志,2005;26(7):477.
[3]郭绶衡,唐青,李浩等.中国31省1991-2005年狂犬病流行情况比较分析[J].中华流行病学杂志,2007;28(4):374-376.
[4]梁海荣,唐焕文,李华文等. 2463例狂犬病疫苗免疫后抗体水平及其影响因素分析[J].中国人兽共患病杂志,2003;19(6):118.
[5]徐伏牛,任军,许明德等.流行病学调查表备览[M].安徽:科学技术出版社,2004:61-67.
[6]Laiskonis A, Bareisiene MV, Velyvyte D, et al. Surveillance of animal and human rabies in Lithuania from 1991 to 2001[J]. Med Mal Infect,2006,36(1):4-8.
[7]谢世宏,史秀山,王显军等.狂犬病防治手册[M].四川:科学技术出版社,2003:15~40,219-225.
[8]Bocsan IS,Brumboiu I, Coman A,et al. Rabies surveillance in the rural population of Cluj County,Romania[J].Rural Remote Health,2005,5(3):431.
[9]World Health Organization Department of Communicable Disease Surveillanceand Response. Strategies for the control and eliminationof rabies in Asia.Geneva:The Organization,2001.
[10]Conzelmann KK,Cox JH,Schneider LG,et al. Molecular cloning and complete nucleotide sequence of the attenuated rabies virus SAD B19. Vriology. 1990,175(2):485-99
[11]徐葛林,Li Ku,吴杰等.中国19个狂犬病毒街离分离株N基因的序列分析[J].病毒学报,2002;18(1):48-51.
[12]Picard Meyer E , Bruyere V , Barrat J ,et al. Development of a hemi-nested RT-PCR method for the specific determination of European Bat Lyssavirus 1[J ] . Comparison with other rabies diagnostic methods. Vaccine ,2004,22 (15– 16):921 -1929.
[13]Meslin FX.Kaplan MM.Koprowski H.Laboratory techniquesin rabies[M].Fourthedition,WTO,Geneva.1996,88-95
[14]Badrane H,Bahloul C,Perrin P,et al.Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity.Virol.2001,27:3268-3276
[15]Qi Liu,Yi Xiong,Ting Rong Luo,et al. Molecular epidemiology of rabies in Guangxi Province, south of China. [J]Journal of Clinical Virology,2007,39 (4):295-303.
[16]S. Vázquez-Morón,A. Avellón, J.E. Echevarría. RT-PCR for detection of all seven genotypes of Lyssavirus genus. [J]Journal of Virological Method,2006,135 (2):281-287.
[17] Ajayi Bb,Rabo JS,Baba SS. Rabies in apparently healthy dogs:histological and immunohistochemical studies[J]. Niger Postgrad Med J,2006,13(2):128-134.
[18]ErmineA.1.arzulD,Guesdon J I, et al. PCR amplification of rabies virus nucleic acids from toialnlousebrainRNA.MoleeulCellulProb.1990.4:189- 191.
[19]SaeralnentoD.PCRteehniqueasanaltemativemethod fordiagiagnosis and molecular pidemio]ogy of rabies virus. Moleeul Celhd Prolz.1991.5:229-240.
[20]KamolvarinN.Tirawatnpong T.RatlanasiwamokeR,etal.Diagnosis of rabies by polymerase Chainreaction with nested primers.J lnf Dis, 1993.167:207-210.
[21]罗廷荣,源宣之等,NestedPCR检测狂犬病毒方法的建立及病毒在小鼠体内的多行动态,中国兽医学报,2000,20(6),535-538.
[22]Tordo N,Poch O,Ermine A,et al. Completion of the rabies virus genome sequence determination:highly conserved domains among the L(polymerase)proteins of unsegmented negative-strand RNA viruses. [J]. Virology. 1988,165(2):565-76.
[23]W illiam H W unner, Jovi K L arson, Bernhard D ietzschold,et al. The molecular biology of rabies viruses. [J].Review s of infectious diseases,1988,Vo l. 10,Supplement 4:S771- S784
[24]杨淑君.北京又增10万条狗. [2007-08-07].http://www.bj.xinhuanet.com/bjfs/2007-08/07/content_10792158.htm
[25] Yelverton E, Norton S, Obijeski JF, et al.Rabies virus glycoprotein analogs: biosynthesis in Escherichia coli[J]. Science,1983,219(4585):614-20.
[26] Klepfer SR, Debouck C, Uffelman J, et al.Characterization of rabies glycoproteinexpressed in yeast[J]. Arch Virol,1993:128(3-4):269-86.
[27] Yokomizo AY, Jorge SA, Astray RM, et al. Rabies virus glycoprotein expression in Drosophila S2 cells. I. Functional recombinant protein in stable co-transfected cell line.[J]. Biotechnol J,2007,2(1):102-109.
[28] Hu R, Zhang S, Fooks AR, et al. Prevention of rabies virus infection in dogs by a recombinant canine adenovirus type-2 encoding the rabies rirus glycoprotein[J]. Microbes Infec,2006,8(4):1090-1097.
[29]Prehaud C,Coulon P,LaFay F,et al. Antigenic site II of the rabies virus glycoprotein:structrue and role in viral virulence[J]. J Virol,1988,62(1):1
[30]Delwart E L, E G Shpaer, J I Mullins, et al. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes[J].Science ,1993,262:1257-1261.
[1]唐家琪.自然疫源性疾病[M].北京：科学出版社，2005：358.
[2]World Health Organization Department of Communicable Disease Surveillanceand Response.Strategies for the control and eliminationof rabies in Asia.Geneva:The Organization,2001.
[3] Tang XC,Luo M,Zhang SY,et al.Pivotal role of dogs in rabiestransmission,China.Emerging Infectious Diseases,2005,1 1(12): 1970-1972.
[4]俞永新主编，狂犬病和狂犬病疫苗，中国医药科技出版社，2001
[5]KawaiA,AnzaiJ,HondaY,et al.Monoclonal antibody recognizes the phosphatase-sensitive epitope of rabies virus nucleoprotein.MicrobiolImmunol. 1997,41(1):33-42
[6]Raux H,Flamand A,Blondel D.Interaction of the rabies virus P protein with theLC8 dynein light chain.Journal of Virology.2000,74(21): 10212-6.
[7]Mebatsion T,Weiland F,Conzelmann KK.Matrix protein of rabies virus isresponsible for the assembly and budding of bullet-shaped particles and interacts withthe transmembrane spike glycoprotein G. Journal of Virology. 1999,73(1):242-50.
[8]Harty RN,Paragas 1,Sudol M.Palese P A proline-rich motif within the matrixprotein ofvesicular stomatitis virus and rabies virus interacts with WW domains ofcellular proteins:implications for viral budding. Journal of Virology. 1999,73(4):2921-9
[9]Schoehm G,Iseni F,Mavrakis M,Blondel D,Ruigrok R W.Sreucture of recombinantrabies virus nucleoprotein-RNA complex and identification of the phosphoproteinbinding site.Virol,2001,75(1):490-498.
[10]Ashim K.Gupta,Danielle Blondel,Suresh Choudhary,Amiya K Banerjee.ThePhosphoprotein of Rabies Virus Is Phosphoprotein by a Unique Cellular ProteinKinase and Specific Isomers of Protein Kinase C. Journal of Virology.2000, 1:91-98.
[11]Harty R N,Paragas J,Sudol M,Palese P.A praline-rich motif within matrix proteinof vescular stomatitis virus and rabies virus interacts with WW domains of cellularproteins:implication for viral budding. Virol, 1999,73(4):2921-2929.
[12]Mebatsion T,Weiland F,Conzelmann K.Matrix protein of rabies virus isresponsible for the assembly and budding of bullet-shaped particles and interacts withthe transmembrane spike glycoprotein G.Virol, 1999,73(1):242-250.
[13]Morimoto K,Foley HD,McGettigan JP,Schnell MJ,Dietzschold B. Reinvestigationof the role of the rabies virus glycoprotein in viral pathogenesis using a reversegenetics apptoach.Neurovirol.2000,6(5):373-381.
[14]金奇主编.医学分子病毒学.北京：科学出版社，2001，381~390.
[15]Bunschoten H,Gore M,Claassen IJ,et al.Characterization of a newvirus-neutralizing epitope that denotes a sequential determinant on the rabies virusglycoprotein.Journal of General Virology. 1989,70(2):291-8.
[16]Dietzschold M,gore M,MarchadierD et al. Structural and immunologicalcharcterization of a linear virus neutralizing epitope of the rabies virus glycoproteinand its possible use in a synthetic vaccine.Journal of Virology. 1990, 64:3804.
[17]van der Heijden RW,Langedijk JP,Groen J,et al.Structural and functional studieson a unique linear neutralizing antigenic site(G5)of the rabies virus glycoproteinJournal of General Virology.1993,74(8):1539-45.
[18]Macfarlan RI,Dietzschold B,Wiktor TJ,et al.T cell responses to cleaved rabiesvirus glycoprotein and to synthetic peptides.Journal of immunology. 1984,133(5):2748-52.
[19]Morimoto K,Foley HD,McGettigan JP,et al.Reinvestigation of therole of therabies virus glycoprotein in viral pathogenesis using a reverse genetics approach.Journal of neurovirology.2000,6(5):373-81.
[20]Schnell MJ,Conzelmann KK.Polymerase activity of in vitro mutated rabies virusLprotein.Virology.1995,20;214(2):522-30.
[21]Morimoto K,Ni YJ,Kawai A.Syncytium formation is induced in the murineneuroblastoma cell cultures which produce pathogenic type G proteins of the rabiesvirus.Virology.1992,189(1):203-16.
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