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1、,Medical Microbiology,Department of Microbiology,HMU,第37章 肝炎病毒Hepatitis viruses,微生物学教研室 凌 虹,第二篇 致病性细菌,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,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,肝炎病毒
2、（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,Viral Hepatitis-Historical Perspectives,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,Anti-HAV Prevalence,High,In
3、termediate,Low,Very Low,Geographic Distribution of HAV infection,生物学性状,HAV为球形颗粒，直径2732nm，无包膜。基因组为线状单正链RNA,由VP14四种多肽组成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,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
4、达70%90%,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,甲型肝炎血清学变化过程,Sources of HAV Infection 1983-93,Percentage of Cases,Source:CDC,Viral Hepatitis Surveillance Program,Year,Personal contact,Day care center,Foreign travel,Outbreak,Drug use,40,30,20,10,0,1983,1984,
5、1985,1986,1987,1988,1989,1990,1991,1992,1993,Concentration of HAV in Various Body Fluids,Source:Viral Hepatitis and Liver Disease 1984;9-22J Infect Dis 1989;160:887-890,Feces,Serum,Saliva,Urine,100,102,104,106,108,1010,Infectious Doses per ml,Age-specific Incidence of Hepatitis A 1983-93,Source:CDC,
6、National Notifiable Diseases Surveillance System,Year,Reported Cases(per 100,000),1983,1984,1985,1986,1987,1988,1989,1990,1991,1992,1993,0,5,10,15,20,25,5-14 years,15-24 years,25-39 years,0-4 years,40+years,Endemicity,Disease,Rate,Peak Age,of Infection,Transmission Patterns,High,Low to,High,Early,ch
7、ildhood,Person to person;,outbreaks uncommon,Moderate,High,Late,childhood/,young adults,Person to person;,food and waterborne,outbreaks,Low,Low,Young adults,Person to person;,food and waterborne,outbreaks,Very low,Very low,Adults,Travelers;outbreaks,uncommon,Global Patterns of Hepatitis A Virus Tran
8、smission,诊断（Laboratory Diagnosis）,Acute infection is diagnosed by the detection of HAV-IgM in serum by EIAPast Infection i.e.immunity is determined by the detection of HAV-IgG by EIA,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,Many cases occur in community-wide outbreaksno risk factor
9、identified for most caseshighest attack rates in 5-14 year oldschildren serve as reservoir of infectionPersons at increased risk of infectiontravelershomosexual meninjecting drug users,Hepatitis A Vaccination StrategiesEpidemiologic Considerations,Pre-exposuretravelers to intermediate and high HAV-e
10、ndemic regionsPost-exposure(within 14 days)Routinehousehold and other intimate contactsSelected situationsinstitutions(e.g.,day care centers)common source exposure(e.g.,food prepared by infected food handler),Hepatitis A Prevention-Immune Globulin,Group,Age,No.,Doses,EL.U.*(ml),Schedule,(months),Chi
11、ldren and,adolescents,2-18 years,3,360(0.5),0,1,6-12,Adults,18 years,2,1,440(1.0),0,6-12,Doses,HAVRIX,*ELISA units,Recommended Doses&Schedules of HAV Vaccination,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3.5亿,1983年将HBV及
12、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）,HBsAg Prevalence,8%-High,2-7%-Intermediate,2%-Low,Geographic Distribution of Chronic HBV Infection,形态与结构,电镜检查血清标本可见小球形颗粒（22nm）、管形颗粒（22nmx50
13、700nm）、大球形颗粒（42nm）,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,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,HBV复制周期,
14、HBV Replication,HBV,2.4 KB,3.5 KB,Provirus,RT,Replicate,Nuclear,2.1 KB,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/r4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,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H
15、Bc，特别是抗HBc IgM表示HBV再肝内处于增殖状态,HBVe抗原（HBeAg）由PreC和C基因共同编码，15KDHBcAg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,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,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
16、用，有保护作用,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,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,Incubation period:Average 60-90 daysRange 45-180 daysClinical 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%P
17、remature mortality fromchronic liver disease:15%-25%,Hepatitis B-Clinical Features,Spectrum of Chronic Hepatitis B Diseases,Chronic Persistent Hepatitis-asymptomaticChronic Active Hepatitis-symptomatic exacerbations of hepatitisCirrhosis of LiverHepatocellular Carcinoma,High(8%):45%of global populat
18、ionlifetime risk of infection 60%early childhood infections commonIntermediate(2%-7%):43%of global populationlifetime risk of infection 20%-60%infections occur in all age groupsLow(2%):12%of global populationlifetime risk of infection 20%most infections occur in adult risk groups,Global Patterns of
19、Chronic HBV Infection,High,Moderate,Low/NT,blood,semen,urine,serum,vaginal fluid,feces,wound exudates,saliva,sweat,tears,breastmilk,Concentration of Hepatitis B Virus in Various Body Fluids,Modes of Transmission of HBV,Sexual sexual and homosexuals are particular at riskParenteral Intravenous drug a
20、buse(IVDA),Health Workers are at increased riskPerinatalMothers 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,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
21、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%）,*Includes sexual contact with acute cases,carriers,and multiple partners.Source:CDC Sentinel Counties Study of Viral Hepatitis,Heterosexual*(41%),Homosexual Activity(9%),Household Cont
22、act(2%),Health Care Employment(1%),Other(1%),Unknown(31%),InjectingDrug Use(15%),Risk factors for Acute Hepatitis B1992-1993 USA,Source:CDC Viral Hepatitis Surveillance Program,0-14,15-19,20-29,30-39,40+,0,5,10,15,20,25,Rate of Reported Hepatitis B by Age Group USA 1990,Age Group(years),Rate(/100,00
23、0),Exposure,Infection,Death 1%Fulminanthepatitis,Recovery90%-95%Immune,Asymptomatic CarrierPersistent InfectionChromic hepatitis,Chronic active hepatitisCirrhosisHepatocellular carcinoma,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,细胞免疫损伤细胞免疫强弱与临床过程轻重与转归密切相关免疫力过强可出现重症肝炎，过低则是慢性肝炎体液免疫损伤：不十分重要先天性无丙种球蛋白血
24、症患者乙肝仍表现为典型的肝炎病变抗原抗体复合物超敏反应，造成了肝外症状表现自身免疫损伤HBV感染后，肝细胞自身表面抗原肝特异性脂蛋白抗原（Liver specific protein,LSP）暴露,HBV与原发性肝细胞癌,乙肝患者原发性肝癌发生率比对照高原发性肝癌患者有HBV感染标志者比自然人群多HBV感染者比阴性者发生原发性肝癌的危险性高217倍WHV可诱导土拨鼠肝硬化及原发性肝癌新生土拨鼠感染WHV三年后100%发生肝癌未感染鼠则无一只发生肝癌肝癌细胞DNA整合有HBV-DNA,免疫性,体液免疫HBV的中和抗体抗HBs抗Pre-S2细胞免疫CTL是清除细胞内病毒的主要机制细胞免疫处于较低水
25、平则易转为慢性,微生物学检查法,病毒核酸的检测斑点杂交法，PCR，极敏感的方法，临床常规对血清病毒DNA浓度可做动态监测HBV抗原、抗体的检测最敏感方法是RIA、ELISA检测项目HBsAg和抗-HBsHBeAg和抗-Hbe抗-HBcIgM和抗HBc-IgG,Symptoms,HBeAg,anti-HBe,Total anti-HBc,IgM anti-HBc,anti-HBs,HBsAg,0,4,8,12,16,20,24,28,32,36,52,100,Typical Serologic Course,Weeks after Exposure,Titre,Acute Hepatitis B
26、 Virus Infection with Recovery,IgM anti-HBc,Total anti-HBc,HBsAg,Acute(6 months),HBeAg,Chronic(Years),anti-HBe,0,4,8,12,16,20,24,28,32,36,52,Years,Weeks after Exposure,Titre,Progression to Chronic Hepatitis B Virus Infection,Typical Serologic Course,HBsA：表示机体感染了HBV急性乙型肝炎潜伏期和急性期（70%）HBV所致的慢性肝病如慢性乙型肝炎
27、、肝硬化和原发性肝炎无症状HBsAg携带者抗HBs机体曾感染过HBV，并获得对HBV的免疫力,HBcAg：常规方法难以检出，临床不做抗HBc抗HBc IgM出现于急性乙型肝炎急性期抗HBc IgG阳性表示过去感染过HBV，少数也可能仍有HBV感染,HBeAg：体内HBV复制和血液传染性强急性乙肝HBeAg呈短暂阳性，如持续阳性提示转为慢性，预后不良孕妇HBeAg阳性，新生儿感染率高抗Hbe见于急性乙肝的恢复期，可持续较长时间机体获得一定免疫力,Pre-S1、Pre-S2和PHSA受体HBV新感染的标志，检出表示HBV正在复制抗Pre-S1、抗Pre-S2中和病毒出现于急性乙肝恢复早期消失较快,
28、Examples of Serology Test,预防原则,要采取切断传播途径为主的综合性措施自动免疫：HBsAg疫苗（血源或重组）被动免疫：乙肝免疫球蛋白(HBIg)。接种者:医务人员或实验室工作人员HBsAg、HBeAg阳性母亲的新生儿发现已误用HBsAg阳性的血液或血制品者与HBsAg、HBeAg阳性者有密切性接触者,Elimination of HBV Transmission,Prevent perinatal HBV transmissionRoutine vaccination all infantschildren in high-risk groupsadolescents
29、all unvaccinated children at 11-12 yearsadults in high-risk groups,Vaccinelicensed,HBsAg screeningof pregnant women recommended,Infantimmunizationrecommended,Adolescent immunization recommended,Decline among homosexual men&HCWs,Decline among injectingdrug users,80,70,60,50,40,30,20,10,0,78,79,80,81,
30、82,83,84,85,86,87,88,89,90,91,92,93,94,95,Year,Cases per 100,000 Population,Estimated Incidence of Acute Hepatitis B,USA 1978-1995,Hepatitis C virus,1978年WHO将非甲非乙型肝炎病毒按传播途径分为肠道传播的非甲非乙型病毒和肠道外传播的非甲非乙型肝炎病毒1989年进一步将前者命名为戊型肝炎病毒（HEV），将后者命名为丙型肝炎病毒（HCV）目前拟将HCV和庚型肝炎病毒（HGV）列入黄病毒科（Flavivurus）Hepacivirus属,生物学性状
31、,HCV属于黄病毒科，电镜照片不清晰，似球形，直径5565 nm，有脂蛋白包膜，包膜上有短突起。核酸为+ssRNA，9.4Kb,由于不能培养，故尚不能进行血清分型据基因序列同源性，分为I VI六个基因型。中国和亚洲流行多型，欧美为I 型细胞培养未成功黑猩猩是唯一易感动物,hypervariableregion,capsid,envelopeprotein,protease/helicase,RNA polymerase,c22,5,core,E1,E2,NS2,NS3,33c,NS4,c-100,NS5,3,Hepatitis C Virus Genome,HCV基因结构,Hepatitis
32、C-Clinical Features,潜伏期 平均6-7周（2-26周）急性表现（黄疸）轻微(20%)急性期死亡率 低慢性感染率75%-85%慢性肝炎70%肝硬化10%-20%慢性肝脏疾病导致死亡1%-5%,Chronic Hepatitis C Infection,The spectrum of chronic hepatitis C infection is essentially the same as chronic hepatitis B infectionAll the manifestations of chronic hepatitis B infection may be
33、seen,albeit with a lower frequency i.e.chronic persistent hepatitis,chronic active hepatitis,cirrhosis,and hepatocellular carcinoma,病理,HCV不直接杀伤细胞病理免疫和细胞凋亡是造成伤害原因,Transmission of HCV,Percutaneous Intravenous drug abuseTransfusion,transplant Therapeutic(contaminated equipment,unsafe injection practice
34、s)PermucosalPerinatalSexual,Sources of Infection forPersons with Hepatitis C,Sexual 15%,Other*5%,Unknown 10%,Injecting drug use 60%,Transfusion 10%(before screening),*Nosocomial;Health-care work;Perinatal,Source:Centers for Disease Control and Prevention,HCV Prevalence by Selected Groups,USA,Hemophi
35、lia,Injecting drug users,Surgeons,PSWs,Hemodialysis,Average Percent Anti-HCV Positive,Gen population adults,Military personnel,STD clients,Pregnant women,Prevalence of HCV Infection by Age&Gender,1988-1994 USA,Males,Females,Source:CDC,NHANES III,Total,Perinatal Transmission of HCV,Transmission only
36、from women HCV-RNA positive at deliveryAverage rate of infection 6%Higher(17%)if woman co-infected with HIVNo association withDelivery methodBreastfeedingInfected infants do wellSevere hepatitis is rare,*Reported in U.S.,Household Transmission of HCV,Rare but not absentCould occur through percutaneo
37、us/mucosal exposures to bloodTheoretically through sharing of contaminated personal articles(razors,toothbrushes)Contaminated equipment used for home therapiesInjections*Folk remedies,Serologic Pattern of Acute HCV Infection with Recovery,Symptoms+/-,Time after Exposure,Titer,anti-HCV,ALT,Normal,0,1
38、,2,3,4,5,6,1,2,3,4,Years,Months,HCV RNA,Serologic Pattern of Chronic HCV Infection with Progression Infection,Symptoms+/-,Time after Exposure,Titer,anti-HCV,ALT,Normal,0,1,2,3,4,5,6,1,2,3,4,Years,Months,HCV RNA,Laboratory Diagnosis,HCV antibody-generally used to diagnose hepatitis C infection.Not us
39、eful in the acute phase as it takes at least 4 weeks after infection before antibody appears.HCV-RNA-various techniques are available e.g.PCR and branched DNA.May be used to diagnose HCV infection in the acute phase.However,its main use is in monitoring the response to antiviral therapy.HCV-antigen-
40、an EIA for HCV antigen is available.It is used in the same capacity as HCV-RNA tests but is much easier to carry out.,HCV Infection Testing Algorithmfor Diagnosis of Asymptomatic Persons,EIA for Anti-HCV,Negative(non-reactive),STOP,Positive(repeat reactive),OR,RIBA for Anti-HCV,RT-PCR for HCV RNA,Ne
41、gative,STOP,Additional Laboratory Evaluation(e.g.PCR,ALT),Negative,Positive,Indeterminate,Medical Evaluation,Positive,Negative PCR,Normal ALT,Positive PCR,Abnormal ALT,Source:MMWR 1998;47(No.RR 19),Routine HCV Testing Not Recommended(Unless Risk Factor Identified),Health-care,emergency medical,and p
42、ublic safety workers Pregnant women Household(non-sexual)contacts of HCV-positive persons,Screening of blood,organ,tissue donorsHigh-risk behavior modificationBlood and body fluid precautions,Prevention of Hepatitis C,Estimated Incidence of Acute HCV Infection,1960-1999 USA,Decline intransfusion rec
43、ipients,Decline in injection drug users,Source:Hepatology 2000;31:777-82 Hepatology 1997;26:62S-65S,Posttransfusion Hepatitis C,All volunteer donors,HBsAg,Donor Screening for HIV Risk Factors,Anti-HIV,ALT/Anti-HBc,Anti-HCV,Improved HCV Tests,Adapted from HJ Alter and Tobler and Busch,Clin Chem 1997,
44、Treatment,Interferon-may be considered for patients with chronic active hepatitis.The response rate is around 50%but 50%of responders will relapse upon withdrawal of treatment.Ribavirin-there is less experience with ribavirin than interferon.However,recent studies suggest that a combination of inter
45、feron and ribavirin is more effective than interferon alone.,Hepatitis D virus,肝炎病毒（Hepatitis virus）从HBV感染者中发现的,HDV Prevalence,High,Intermediate,Low,Very Low,No Data,Taiwan,Pacific Islands,Geographic Distribution of HDV Infection,生物学性状,3537nm，球形颗粒环状单股负链RNA和HDAg（即抗原）1.7Kb表面为HBV包膜蛋白（HBsAg）,HBsAg,RNA,d
46、 antigen,HDV为缺陷病毒不能独立进行复制，必须在HBV或其它嗜肝DNA病毒辅助才能增殖敏感动物黑猩猩，土拨鼠和北京鸭等,Hepatitis D-Clinical Features,Coinfectionsevere acute diseaselow risk of chronic infectionSuperinfectionusually develop chronic HDV infectionhigh risk of severe chronic liver diseasemay present as an acute hepatitis,HDV Transmission,Pe
47、rcutanous exposuresinjecting drug usePermucosal exposuressex contact,免疫性,抗HDV 不能清除病毒，为诊断指标HDV IgM和IgG持续存在，提示为HDV慢性感染,Time after Exposure,Titer,anti-HBs,Symptoms,ALT Elevated,Total anti-HDV,IgM anti-HDV,HDV RNA,HBsAg,Serological Course of Acute HDV infection,Time after Exposure,Titer,Jaundice,Symptom
48、s,ALT,Total anti-HDV,IgM anti-HDV,HDV RNA,HBsAg,Serological Course of HDV superinfection,微生物学检查法,血清学方法ELISA检查HDAg或抗HDVHDAg在急性期可阳性，检出率低慢性感染检不到核酸分子杂交法,HBV-HDV CoinfectionPre or postexposure prophylaxis to prevent HBV infection.HBV-HDV SuperinfectionEducation to reduce risk behaviors among persons with
49、 chronic HBV infection.,Hepatitis D-Prevention,Hepatitis E virus，HEV,戊型肝炎病毒经肠道传播的非甲非乙型肝炎病毒疾病：戊型肝炎,Geographic Distribution of Hepatitis E,生物学性状,HEV呈球形，直径2738nm核酸为线形（-）ssRNA无包膜，20面体立体对称现分类于杯状病毒只有一个血清型易感动物非洲绿猴、恒河猴、黑猩猩,致病性,粪口途径传播水源污染造成流行，极小生活接触导致感染多感染2040岁成人潜伏期29周，临床表现为急性肝炎，6周即恢复少数重症死亡。无慢性感染病例致病机理不明免疫损伤
50、是主要机制。病后有一定免疫力,Weeks after Exposure,Titer,Symptoms,ALT,IgG anti-HEV,IgM anti-HEV,Virus in stool,0,1,2,3,4,5,6,7,8,9,10,11,12,13,Serological Course of HEV infection,微生物学检查法,免疫电镜血清学方法，检测抗-HEVHEV核酸检测,Prevention and Control Measures for Travelers to HEV-Endemic Regions,Avoid drinking water(and beverages
