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Medical Microbiology

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  1. Medical Microbiology Department of Microbiology, HMU

  2. 第二篇 致病性细菌 第37章 肝炎病毒 Hepatitis viruses 微生物学教研室 凌 虹

  3. 教学大纲 • 掌握内容 • 肝炎病毒的种类 • 乙型肝炎病毒形态结构、致病性、预防原则 • 熟悉内容 • 丁型肝炎病毒结构特征及致病特点 • 戊型肝炎病毒传播途径及致病特点

  4. 问题 • 肝炎病毒有哪些? • 甲型肝炎病毒的传播方式、致病特点和预防原则 • 简述乙型肝炎病毒的生物学性状、抗原抗体组成及检出的意义、传播方式、致病特点及预防原则 • 丙型肝炎病毒的生物学特点和致病特点 • 丁型肝炎病毒(HDV)的概念 • 简述戊型肝炎病毒传播方式和致病特点

  5. 肝炎病毒(Hepatitis virus) • 以侵害肝脏为主引起病毒性肝炎的病毒 • 种类: • 甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)、GBV-C/HGV、TTV • 其他病毒 • 黄热病毒、CMV、EBV、风疹病毒等

  6. Enterically transmitted “Infectious” A E Viral hepatitis NANB Parenterally transmitted B D C “Serum” F, G, TTV ? other Viral Hepatitis - Historical Perspectives

  7. Hepatitis A virus • 1973年Feinstone • 应用免疫电镜技术从急性肝炎患者粪便发现 • 生物学性状与肠道病毒一致 • 1982年国际病毒命名委员会将它分类为小核糖核酸病毒科肠道病毒属72型

  8. Geographic Distribution of HAV infection Anti-HAV Prevalence High Intermediate Low Very Low

  9. 生物学性状 • HAV为球形颗粒,直径27~32nm,无包膜。基因组为线状单正链RNA

  10. 由VP1~4四种多肽组成 • VP1是主要衣壳蛋白和中和抗原,能中和所有HAV • 细胞培养:HAV可用猴肾、人胚肾细胞等进行增殖和传代,但不引起CPE • 易感动物有黑猩猩、南美洲猴、猕猴等 • 接种后可出现急性肝炎 • 抵抗力:较强 • 对乙醚、酸、热(60oC)稳定。高压、紫外、煮沸等可灭活

  11. 流行病学 • 传染源 • 患者和隐性感染者 • 传播方式:粪-口途径 • 污染食物、水源、海产品引起暴发或散发流行 • 隐性感染率高 • 成人HAV抗体阳性率高达70%—90%

  12. 致病性 • 非溶细胞型病毒,不直接杀伤细胞 • 病毒复制量与症状严重程度不一致,故认为免疫应答参与损伤过程 • 病后期粪便可检出sIgA抗体 • 无慢性病例 • 典型的甲肝是自限过程,大约三个月

  13. 甲型肝炎血清学变化过程

  14. Sources of HAV Infection 1983-93 40 30 Personal contact Percentage of Cases 20 Day care center 10 Foreign travel Drug use Outbreak 0 1985 1987 1988 1989 1990 1991 1992 1993 1983 1984 1986 Year Source: CDC, Viral Hepatitis Surveillance Program

  15. Concentration of HAV in Various Body Fluids Feces Serum Saliva Urine 102 104 100 106 108 1010 Infectious Doses per ml Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890

  16. Age-specific Incidence of Hepatitis A 1983-93 25 20 15 5-14 years Reported Cases (per 100,000) 15-24 years 25-39 years 10 0-4 years 5 40+ years 0 1983 1984 1985 1987 1988 1989 1990 1991 1992 1993 1986 Year Source: CDC, National Notifiable Diseases Surveillance System

  17. Global Patterns of Hepatitis A Virus Transmission Disease Peak Age Endemicity Rate of Infection Transmission Patterns High Low to Early Person to person; High childhood outbreaks uncommon Moderate High Late Person to person; childhood/ food and waterborne young adults outbreaks Low Low Young adults Person to person; food and waterborne outbreaks Very low Very low Adults Travelers; outbreaks uncommon

  18. 诊断(Laboratory Diagnosis) • Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA • Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA

  19. 防治原则 • 加强食品卫生管理,水源 • 减毒疫苗株H2株和L1株已投放市场 • 基因工程疫苗也正在研究之中 • 应急预防可用丙种球蛋白

  20. Hepatitis A Vaccination Strategies Epidemiologic Considerations • Many cases occur in community-wide outbreaks • no risk factor identified for most cases • highest attack rates in 5-14 year olds • children serve as reservoir of infection • Persons at increased risk of infection • travelers • homosexual men • injecting drug users

  21. Hepatitis A Prevention - Immune Globulin • Pre-exposure • travelers to intermediate and high HAV-endemic regions • Post-exposure (within 14 days) Routine • household and other intimate contacts Selected situations • institutions (e.g., day care centers) • common source exposure (e.g., food prepared by infected food handler)

  22. Recommended Doses & Schedules of HAV Vaccination HAVRIXâ Doses No. Schedule Group Age Doses EL.U.* (ml) (months) Children and 3 360 (0.5) 0, 1, 6-12 adolescents 2-18 years Adults >18 years 2 1,440 (1.0) 0, 6-12 *ELISA units

  23. Hapatitis B Virus • 1963年Blumberg在多次输血的血友病患者中发现澳抗,1968年确与血清型肝炎高度相关,1970年Dane在电镜下看到具有传染性的42nm病毒颗粒 • HBV在亚洲广泛流行,在中国约10%人口携带该病毒,全球约3.5亿

  24. 1983年将HBV及与其分子结构、生物学特性相似的土拨鼠肝炎病毒(woodchuck hepatitis virus,WHV)、地松鼠肝炎病毒(ground squirrel hepatitis virus,GSHV)及鸭肝炎病毒(duck hepatits virus,DHV)归纳起来独立命名为嗜肝病毒科(Hepadnaviridae)

  25. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ³8% - High 2-7% - Intermediate <2% - Low

  26. 形态与结构

  27. 电镜检查血清标本可见小球形颗粒(22nm)、管形颗粒(22nmx50—700nm)、大球形颗粒(42nm)电镜检查血清标本可见小球形颗粒(22nm)、管形颗粒(22nmx50—700nm)、大球形颗粒(42nm)

  28. 完整的HBV颗粒亦称Dane颗粒,颗粒直径为42nm • 具有双层衣壳结构。外壳相当于包膜,由脂质双层和乙肝表面抗原(HBsAg)、多聚人血清白蛋白受体(PHSA-r)和前S抗原(Pre-S)组成。内部有28nm的核心,表面相当于内衣壳,含有乙型肝炎核心抗原(HBcAg)和乙型肝炎e抗原(HBeAg)。内部有HBV的DNA和DNA多聚酶

  29. HBV 基因组 • DNA是由3.2KB的长链 L(-)和短链 S(+)(约为L链的50%至85%长)组成的不完全双链环状DNA,长链载有病毒蛋白质的全部密码,有4个开放读码框架(ORF),分别称为S、C、P和X区

  30. HBV复制周期

  31. HBV Replication Nuclear 2.1 KB 2.4 KB HBV 3.5 KB Provirus Replicate RT

  32. 抗原组成 • HBV表面抗原(HBsAg) • 是机体受HBV感染的标志 • 226AA,由S基因编码 • HBsAg有1个共同抗原决定簇a和2组互相排斥的亚型抗原决定簇d/y和w/r • 4种亚型:adr、adw、ayr、 ayw • 我国内地和沿海各省汉族主要为adr型,欧美为adw • 抗HBs • 能与HBV表面结合,使其失去感染性,具有保护作用

  33. HBV核心抗原(HBcAg) • 在肝细胞核中才能检出 • 分子量22KD,由C基因编码,病毒内衣壳蛋白 • 一般方法在血中检测不到 • 抗HBc • 无中和作用 • 检出高效价抗HBc,特别是抗HBc IgM表示HBV再肝内处于增殖状态

  34. HBVe抗原(HBeAg) • 由PreC和C基因共同编码,15KD • HBcAg在细胞经蛋白酶降解形成 • HBV复制及血清有传染性的标志 • 抗Hbe • 对HBV感染有一定保护作用

  35. 前S抗原(Pre-S Ag) • 前S2蛋白 • S + PreS2编码,226 + 55=281AA • 前S1蛋白 • S + PreS2 + PreS1编码,226 + 55 + 119 = 400AA • 与HBsAg、HBV DNA检出相同,都说明病毒在复制

  36. Pre-S2抗原 • 和人肝细胞表面都具有PHSA受体,通过PHSAr搭桥,HBV病毒易吸附于肝细胞表面 • 部分解释为什么HBV具有嗜肝细胞性 • 抗前S1和抗前S2抗体 • 具有中和HBV作用,有保护作用

  37. 易感动物和细胞培养:只有黑猩猩对HBV易感,体外细胞培养尚未成功易感动物和细胞培养:只有黑猩猩对HBV易感,体外细胞培养尚未成功

  38. 抵抗力:强 • 对低温、干燥、UV、醚、氯仿、酚等均有抵抗性 • 高压蒸汽灭菌、0.5%过氧乙酸、5%次氯酸钠、3%漂白粉液、0.2%新洁尔灭均可灭活病毒,但处理时间要稍长

  39. Hepatitis B - Clinical Features • Incubation period: Average 60-90 days Range 45-180 days • Clinical illness (jaundice): <5 yrs, <10%5 yrs, 30%-50% • Acute case-fatality rate: 0.5%-1% • Chronic infection: <5 yrs, 30%-90% 5 yrs, 2%-10% • Premature mortality fromchronic liver disease: 15%-25%

  40. Spectrum of Chronic Hepatitis B Diseases • Chronic Persistent Hepatitis - asymptomatic • Chronic Active Hepatitis - symptomatic exacerbations of hepatitis • Cirrhosis of Liver • Hepatocellular Carcinoma

  41. Global Patterns of Chronic HBV Infection • High (>8%): 45% of global population • lifetime risk of infection >60% • early childhood infections common • Intermediate (2%-7%): 43% of global population • lifetime risk of infection 20%-60% • infections occur in all age groups • Low (<2%): 12% of global population • lifetime risk of infection <20% • most infections occur in adult risk groups

  42. Concentration of Hepatitis B Virus in Various Body Fluids High Moderate Low/NT blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk

  43. Modes of Transmission of HBV • Sexual • sexual and homosexuals are particular at risk • Parenteral • Intravenous drug abuse (IVDA), Health Workers are at increased risk • Perinatal • Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not • Perinatal transmission is the main means of transmission in high prevalence populations

  44. 传染源:急、慢性乙肝患者及无症状携带者 • 传播途径:非胃肠道途径 • 血液、血制品传播 • 输血、丙种球蛋白 • 医源性传播:注射(吸毒)、手术、采血、针刺、拨牙、内窥镜检查、纹身等 • 接触传播:公共卫生洁具、剃刀、吸血昆虫 • 母婴传播 • 宫内感染相对少(<10%) • 母亲HBeAg阳性婴儿感染机会大(90%) • HBeAg阴性、抗HBe阳性婴儿感染机率小(10%—15%)

  45. Risk factors for Acute Hepatitis B1992-1993 USA Heterosexual* (41%) Injecting Drug Use (15%) Homosexual Activity (9%) Household Contact (2%) Health Care Employment (1%) Unknown (31%) Other (1%) * Includes sexual contact with acute cases, carriers, and multiple partners. Source: CDC Sentinel Counties Study of Viral Hepatitis

  46. Rate of Reported Hepatitis B by AgeGroup USA 1990 25 20 Rate (/100,000) 15 10 5 0 0-14 15-19 20-29 30-39 40+ Age Group (years) Source: CDC Viral Hepatitis Surveillance Program

  47. Exposure Recovery 90% - 95% Immune Infection Asymptomatic Carrier Persistent Infection Chromic hepatitis Death 1% Fulminant hepatitis Chronic active hepatitis Cirrhosis Hepatocellular carcinoma

  48. 致病机理 • 尚未完全明了 • HBV不直接损害肝细胞,通过宿主的免疫应答引起肝细胞的损伤和破坏