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Flavivirus

Flavivirus. Xiao-Kui GUO Dept. of Microbiology and Parasitology. 人畜共患病毒性疾病 Viral Zoonosis. 人畜共患病 脊椎动物（ vertebrate animals ） 所患疾病能通过昆虫媒介直接或间接传递给人类 如果有昆虫参与，这个疾病也称为虫媒疾病（ arboviral ） 如狂犬病、肾综合症出血热、流行性乙型脑炎和埃博拉出血热.

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Flavivirus

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  1. Flavivirus Xiao-Kui GUO Dept. of Microbiology and Parasitology

  2. 人畜共患病毒性疾病Viral Zoonosis • 人畜共患病 • 脊椎动物（vertebrate animals）所患疾病能通过昆虫媒介直接或间接传递给人类 • 如果有昆虫参与，这个疾病也称为虫媒疾病（arboviral） • 如狂犬病、肾综合症出血热、流行性乙型脑炎和埃博拉出血热

  3. 虫媒病毒（Arthropod-borne viruses，arboviruses）是通过节肢动物（ arthropod vectors）传播的病毒 • The WHO definition is as follows • Viruses  maintained  in nature principally, or to an important extent, through biological transmission between susceptible vertebrate  hosts by haematophagus arthropods or through  transovarian and possibly venereal transmission in arthropods

  4. 虫媒病毒种类 • 虫媒病毒分属3个病毒科： • Togaviruses（披膜病毒科） • EEE, WEE, and VEE • Bunyaviruses（布尼亚病毒科） • Haemorrhagic Fever • Sandfly Fever, Rift Valley Fever, Crimean-Congo • Flaviviruses（黄病毒科） • Yellow Fever, dengue, Japanese Encephalitis

  5. Prevalence in China • 在我国流行并经病毒分离证实的虫媒病有6种 • 流行性乙型脑炎 • 森林脑炎 • 登革热 • 基孔贡亚热 • 肾综合征出血热 • 新疆出血热

  6. Scientist collecting specimens from trapped rodents

  7. Common characteristics • 40~70 nm in diameter, +ssRNA spherical enveloped • Hemophilic arthropods as vector, and viruses replicate in arthropod • 5 type clinical manifestations and diseases related to season and district.

  8. Major Clinical Categories of Arboviral Disease • No clinical illness. • Febrile systemic illness. • Encephalitis • Haemorrhagic Fever. • Hepatitis • arthritis

  9. Genome

  10. 黄病毒 Flaviviruses • 登革病毒 Dengue viruses • 流行性乙型脑炎病毒 Epidemic type B encephalitis virus • 蜱传脑炎病毒 Tick-borne encephalitis virus

  11. 黄病毒生物学特性 • 球形，20~60nm，个别达100nm，有包膜，+ssRNA基因组，有感染性，只有一个读码框，编码一个大前体蛋白，切割后分成结构和调节蛋白 • 核心由C蛋白和RNA构成二十面体立称核衣壳，包膜上有病毒编码的M和E蛋白，其中E蛋白具有血凝素作用，能凝集鸡红细胞 • 对酸、醚、 氯仿敏感 • 在节肢动物体内增殖，对节肢动物不致病，但通过叮咬传染给脊椎动物和人类，引起自然疫源性的人畜共患疾病：脑炎、黄热病和出血热等 • 致病呈明显的季节性和地区性

  12. 节肢动物媒介Arthropod Vectors • Mosquitoes （蚊） • Japanese encephalitis, dengue, yellow fever, St. Louis encephalitis, etc. • Ticks （蜱） • Crimean-Congo haemorrhagic fever, various tick-borne encephalitis etc. • Sandflies （白蛉） • Sicilian sandfly fever, Rift valley fever.

  13. Arthropod Vectors Aedes Aegyti （伊蚊） Assorted Ticks （蜱） Phlebotmine Sandfly （吸血白蛉） Culex Mosquito （库蚊）

  14. 动物宿主（Reservoirs） In many cases, the actual reservoir is not known. The following animals are implicated as reservoirs • 鸟 • Japanese encephalitis, St Louis encephalitis • 猪 • Japanese encephalitis • 猴 • Yellow Fever • 啮齿类动物 • Russian Spring-Summer encephalitis

  15. 传播环节 • 人 – 节肢动物 – 人 • Dengue • 动物 – 节肢动物 – 人 • Japanese Encephalitis • 混合方式：两种都有 • some arboviruses such as yellow fever

  16. Man-Arthropod-Man Cycle Dengue Reservoir may be in either man or arthropod vector In the latter transovarial transmission may take place

  17. Animal-Arthropod-Man Cycle Japanese encephalitis The reservoir is in an animal,The virus is maintained in nature in a transmission cycle involving the arthropod vector and animal Man becomes infected incidentally

  18. 登革病毒 Dengue Virus • Dengue  is the biggest arbovirus problem in the world today  with over 2 million cases per year • Dengue is found in Southeast Asia, Africa and the Caribbean and S America

  19. Mature Dengue-2 virus particles replicating in five day old tissue culture cells

  20. 传播环节 • Transmitted by Aedes mosquitoes（伊蚊）which reside in water-filled containers • Human infections arise from a human-mosquitoe-human • reservoir: monkey and human beings • occur in both an urban and jungle cycle

  21. 临床特点 • 隐性感染率高 • 登革热 • 高热，淋巴结肿大，肌肉酸痛，骨关节痛疼，头痛，斑丘疹 • 登革出血热、登革休克综合症 • 在再次感染患者中，少数发展成严重的登革出血热（ Dengue haemorrhagic fever ）和登革休克综合症（ Dengue shock syndrome ），死亡率达 5-10% • 发病机机制与机体存在的抗体参与的免疫病理反应有关 • ADE/immune enhancement

  22. A large subcutaneous haemorrhage on the upper arm of a patient with dengue haemorrhagic fever.

  23. Lab Diagnosis • Culture in C6/36 cells: 1-3days • HI: 1 weeks • CFT: • ELISA: IgM ; IgG 5 days:80% 6-10 days : 99%

  24. 预防 • No specific antiviral therapy is available • Prevention of dengue in endemic areas depends on mosquito eradication. The population should remove all containers from their premises which may serve as vessels for egg deposition • A live attenuated vaccine is being tried in Thailand with encouraging results

  25. 流行性乙型脑炎病毒Epidemic Type B Encephalitis • Virus first discovered and originally restricted to Japan (1934), also called Japanese B encephalitits virus • Now large scale epidemics occur in China, India and other parts of Asia.

  26. 病毒性状 • Belongs to Flavivirus • Typical arbovirus particle, 20~30nm spherical • +ssRNA genome • Envelop with hemoagglutinin that can agglutinate RBCs of chicken and pigeon • Only one serotype, can be controlled by vaccine strategy

  27. Biological properties • Small spherical enveloped virus • SP: C; M; E(HA) • Replicates in susceptible animals, embryo eggs and cell culture; • Stable antigenicity; • Sensitive to lipid solvent agents, physical and chemical treatments

  28. Epidemiology • Source of infection: Patients and infected animals, e.g. young pigs • it is mosquito borne • Young Pigs and birds are its natural hosts

  29. 致病性 • Transmitted by culex mosquitoes（库蚊）. Since Culex has a flight range of 20km, all local control measures will fail • The virus is maintained in nature in a transmission cycle involving mosquitoes, birds and pigs • Viruses are preserved in the body and egg of mosquitoes, therefore, mosquitoes are the long-term reservoir（蚊是储存宿主）

  30. Aedes mosquito feeding

  31. 人被带毒的蚊虫叮咬后，绝大多数表现为隐性感染或仅轻微症状。只有少数发生脑炎。人被带毒的蚊虫叮咬后，绝大多数表现为隐性感染或仅轻微症状。只有少数发生脑炎。 • 病毒侵入人体，经两次病毒血症后，播散到全身，10天左右潜伏期，出现发热、寒战及全身症状。0.1%的患者病毒越过血脑屏障进入脑组织，造成脑实质炎症和脑膜病变，临床表现为突然高热、头痛、呕吐、惊厥、昏迷等脑膜刺激症状和脑炎症状。死亡率高达10%—30% • 部分患者恢复后留下精神障碍、运动障碍等后遗症

  32. Pathogenicity and Immunity • Virus reticular endothelial system Viremia Liver or Spleen Viremia CNS encephalitis • Immunity: Long

  33. Laboratory Diagnosis • Serology • Virus isolation • RT-PCR

  34. 血清学诊断 • 血凝抑制试验 Hemoagglutinin Inhibition Test • Screening IgM-HI antibody for early diagnosis, 75% positive in acute patients • If the titer of HI test dropped 4 times after treated with 2-mercaptoethanol, always means IgM positive • 补体结合试验 Complement fixation test • Double serum samples, the titer of the second : the first >4 • The CF antibody of this virus can last only 2 to 4 months, so positive means newly infection

  35. 病毒分离 Virus isolation • Viremia lasts a very short period, it is hard to isolate virus from blood. • Normally, the cerebral spinal fluid and brain tissue are inoculated into suckling mice brain

  36. 预防 Prevention • Control and kill of mosquitoes • Pesticides, elimination of breeding grounds, insect repellants • Prevent animal infection • Vaccination of pigs before the epidemic season • Vaccination • Children under 10-year-old, one month before the epidemic season • Inactivated vaccine（灭活疫苗）, double subcutaneous injections in duration of one week, repeat vaccination one year later

  37. Tick-borne encephalitis virus • 蜱传脑炎病毒 • 森林脑炎病毒（Forest Encephalitis Virus） • 俄罗斯春夏脑炎病毒（Russian Spring-Summer Encephalitis Virus）

  38. Morphology • Typically Flavivirus • Transmitted by tick • Can be found in Russia, Middle Europe, and Germany, Epidemic infection also occurs in northeastern China. Tick is the host and transmitted vector. Cause encephalitis • Incubation : 10-14 days • Diagnosis = JBV • Prevention • Prevent tick-biting is the key procedure • Inactivated virus vaccine is available

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