微生物肝炎病毒课件.ppt

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,Hepatitis viruses and diseases they cause,HAV-hepatitis A(infectious hepatitis),HBV-hepatitis B(serum hepatitis),HCV-hepatitis C(non-A,non-B hepatitis),HDV-hepatitis D(delta hepatitis),HEV-hepatitis E(infectious hepatitis resembles hepatitis A),HGV-(non A-E hepatitis),TTV-(post-transfusion hepatitis),肝炎病毒,甲型肝炎病毒与戊型肝炎病毒由消化道传播，引起急性肝炎，不转为慢性肝炎或慢性携带者。,乙型与丙型肝炎病毒主要由输血、血制品或注射器污染而传播，除引起急性肝炎外，可致慢性肝炎，并与肝硬化及肝癌相关。,丁型肝炎病毒为一种缺陷病毒,庚型肝炎病毒（,HGV）,TT,型肝炎病毒（,TTV）,Pathogenesis of hepatitis viruses,Target organ:,liver,Symptoms:fever,nausea,vomiting,jaundice(,黄疸,),Chronic infections:HBV,HCV,HDV,No specific treatment,Preventing,甲型肝炎病毒,（,hepatitis A virus，HAV）,Shape:,naked,spherical particle with cubic symmetry.,Genome:,linear,positive-sense,single-stranded RNA,One,stable serotype only,Transmission:,fecal-oral(via contaminated food or water),Stable,at low pH,Inactivated,by high temperature(185F or higher),formalin,chlorine,Biological characterization,HAV,的生物学性状,属小,RNA,病毒科，嗜肝病毒属,球形，直径27,nm，,呈20面立体对称，无包膜,ss(+)RNA,，5,端有一其特有的保守序列，可用于制备探针,只有一个血清型,HAV,的结构,Hepatitis A virus transmission,Close personal contact,(e.g.,household contact,sex contact,child day-care centers),Contaminated food,water,(e.g.,infected food handlers),Blood exposure(rare),(e.g.,injection drug use,rarely by transfusion),Pathogenesis,Virus enters via the,gut,;replicates in the,alimentary tract,(,消化道,)and spreads to infect the,liver,where it multiplies in,hepatocytes,.,Viraemia is,transient,.,Virus present in blood and feces 10-12 days after infection.,Virus excretion may continue for up to 3 weeks after onset of symptoms.,HAV,的致病性,粪,-,口途径传播,口咽部或唾液腺中早期增殖,肠道与局部淋巴结中大量增殖,入血并形成病毒血症,肝脏为最终靶器官（病毒直接损伤或免疫病理作用）,通过胆汁随粪便排出体外,NK,细胞杀伤作用,肝细胞溶解,特异性,CTL,杀伤肝细胞,自身特异性免疫应答,干扰素促进,HLA,的表达,加强,Symptomatology,incubation period,:10 to 50 days(mean 30 days),Symptoms,:,-Initial symptoms:,fever,fatigue(tiedness),nausea,loss of appetite,abdominal pain,-Jaundice,Acute infection,never change into chronic infection.,Pregnant women,may develop more severe disease.,Likelihood of symptomatic illness directly related to,age,Children,generally asymptomatic,adults,symptomatic,HAV,感染的时间进程,HAV,感染后的事件典型顺序,甲型肝炎,传染源为病人和隐性感染者,粪口途径传播,通过污染的水源、食物、海产品、食具等传播,常造成散发性流行或大面积流行,主要侵犯儿童和青少年,临床特点,临床上经血传播的甲型肝炎罕见,致病机制主要与免疫病理有关,一般为自限性疾病，预后良好，不发展成慢性肝炎和慢性携带者,HAV,的免疫性,HAV,只存在单一的抗原抗体系统,，,即,HAVAg,和抗-,HAV,无论显性感染还是隐性感染均能诱生出高效价抗-,HAV,抗-,HAV IgM,阳性是甲肝的确诊依据,IgM,抗体在感染后仅持续存于3-6个月，,IgG,抗体则可存在多年,1988,年上海爆发甲肝大流行,Laboratory diagnosis,Acute infection is,diagnosed,by the detection of,HAV-,IgM,in serum by EIA,(enzyme immunoassay),.,Past,i,nfection i.e.immunity is determined by the detection of,HAV-,IgG,by EIA.,Cell culture,-,difficult,and take up to 4 weeks,not routinely performed,Direct,d,etection,-,EM,(electron microscopy),RT-PCR,(reverse transcription-polymerase chain reaction),of feces,c,an detect illness earlier than serology but rarely performed.,Prevention,Avoiding potentially contaminated water or food,Proper hand wash,Chlorine treatment of drinking water,Prophylaxis with immune serum globulin,Killed HAV vaccine,HAV vaccine,The vaccines contain no live virus andare very safe.No serious adverse effects have been reported.Some people have some soreness at the injection site for a few days.,The vaccinesare given in a series of 2 shots.The second is given 6-18 months after the first.The shots can be given at the same time as other vaccines.,Your protection starts about 2-4 weeks after the first shot.The second dose is necessary to ensure long-term protection.,The vaccines are thought to protect from infection for at least 20 years.,The vaccines must be given before exposure to the virus.They do not work after exposure.,Treatment,Rest,Plenty of fluids,Traditional Chinese medicine,Avoiding drugs harmful to liver,Liver transplantation,Lab diagnosis,血清中的,抗,-HAV IgM,是,早期诊断最可靠的血清学指标,流行病学调查可检测抗,HAV IgG,对已接种甲肝疫苗者检测中和型抗,HAV,抗体,直接检测抗原或用分子生物学方法检测病毒,RNA,Prevention,减毒活疫苗,或,灭活疫苗,，,免疫预防对象是未感染者，主要为儿童和与肝炎病人有密切接触者,被动免疫可用丙种球蛋白,Hepatitis B Virus,Shape and structure,Three morphologic forms,Spherical particles,Tubulose,particles,Dane particles-complete particles,incomplete particles,Small Spherical particles,HBsAg-containing,particles,Tubulose particles,Dane,particle,Dane particles,Complete particles,infective HBV,spherical,，,double capsid,outer capsid=envelope,inner capsid,：,HBcAg,、,HBeAg,internal,：,DNA-,circular,double-stranded,DNA polymerase,What are Dane particles?,42 nm spherical particle,the complete infective virion of hepatitis B containing a 27 nm core antigen.,Dane,颗粒的结构,脂质双层,蛋白质（,HBsAg、PreS1、PreS2）,内衣壳,HBcAg HBeAg,核 心,开口环状,dsDNA,DNA,多聚酶（兼有逆转录酶功能）,HBV,的结构,外衣壳,HBV,的基因组结构,dsDNA,长链为负链，短链为正链,两条链的,DNA,的5端构成粘性末端，其两侧有直接重复序列（,DR）,负链含4个,ORF,S,区：,S,、前,S1,和前,S2,基因,C,区：,C,和前,C,基因,P,区：多聚酶基因等,X,区：,X,基因,HBV,的复制,HBV,的抗原组成,表面抗原,HBsAg,核心抗原,HBcAg,e,抗原,HBeAg,表面抗原（,HBsAg）,是糖基化的病毒蛋白,gp27，,存在于三型颗粒中,是,HBV,感染的主要标志,具有抗原性，可刺激机体产生保护性抗体（抗-,HBs,）和细胞免疫反应，是制备疫苗的最主要成分,分亚型（,adr,、adw、ayr、,ayw,）,PreS1、PreS2,抗-,PreS1,和抗-,PreS2,能阻断,HBV,与肝细胞结合而起抗病毒作用,核心抗原（,HBcAg）,为衣壳蛋白,仅存在于,Dane,颗粒中,不易在血液中检出,可在感染的肝细胞表面存在,刺激机体产生抗,HBc，,其中,IgG,为非保护性抗体，抗,HBc IgM,常表明病毒正在复制,e,抗原（,HBeAg）,仅存在于,Dane,颗粒中,游离存在于血液中,为病毒复制及强传染性的指标,产生抗,HBe，,对感染有一定的保护作用，是预后良好的征象,HBV,的其它生物学性状,培养,黑猩猩动物模型、鸭动物模型,用分子生物学技术的细胞培养成功,抵抗力,抵抗力,较强,对低温、干燥、紫外线耐受，不被70乙醇灭活，100,10,分钟、0.5%过氧乙酸、5%次氯酸钠可灭活。,致病性与免疫性,传染源,主要传染源是患者或无症状,HBV,携带者,传播途径,1、血液、血制品等传播,输血、注射、外科或牙科手术、针刺等,2、垂直传播,多发生于胎儿期和围生期，也可通过哺乳传播,3,、性传播,HBV,Modes of Transmission,Having sex without condoms with someone who has hepatitis B,Main Ways to Get Hepatitis B,You can pass hepatitis B to others if you have just gotten the virus(acute hepatitis)or if you are a carrier of the virus(chronic hepatitis).,Sharing needles and syringes,Being born to a mother who has hepatitis B,You can,NOT,get hepatitis B by,shaking hands with an infected person,hugging an infected person,sitting next to an infected person,Pathology of HBV,Causes a spectrum of liver disease,Acute hepatitis,Chronic hepatitis,Chronic Persistent Hepatitis-asymptomatic,Chronic Active Hepatitis-symptomatic exacerbations of hepatitis,Cirrhosis of liver(,肝硬化,),Hepatocellular carcinoma(,肝癌,),Clinical outcomes of Hepatitis B infections,致病与免疫机制,HBV,感染的临床表现呈,多样性。,免疫病理反应,以及,病毒与宿主细胞间的相互作用,是肝细胞损伤的主要原因。,致病与免疫机制,细胞免疫及其介导的免疫病理反应,途径有三：,1、CTL,的直接杀伤作用,2、T,细胞产生和分泌多种细胞因子,3、CTL,诱导的肝细胞凋亡作用,在清除病毒同时又导致肝细胞损伤,致病与免疫机制,体液免疫及其介导的免疫病理反应,1、,产生抗,HBsAb、PreS1-Ab,和,PreS2-Ab,等保护性中和抗体，清除游离病毒、阻断病毒黏附,2、形成抗原抗体复合物，导致,III,型超敏反应，主要导致肝外损害,致病与免疫机制,自身免疫反应引起的病理损害,HBV,感染肝细胞后,，,暴露出肝特异性脂蛋白抗原（,LSP,，,Liver specific protein,），可作为自身抗原诱导机体产生自身抗体，通过,ADCC,作用、,CTL,的杀伤作用或释放淋巴因子等作用，导致肝细胞损伤。,致病与免疫机制,免疫耐受与慢性肝炎,当,HBV,感染者特异性免疫处于较低水平或完全缺乏时，机体既不能有效地清除病毒，也不能产生有效的免疫应答杀伤靶细胞，病毒与宿主之间和平共处，形成免疫耐受，临床上表现为无症状携带者和慢性持续性肝炎。,免疫应答强弱与临床表现及转归关系,病毒数量不多，应答正常,急性肝炎,痊愈,病毒数量多，应答过高,重症肝炎,死亡率高,病毒不断复制及释放，应答过低,慢性肝炎,肝硬化,病毒变异与免疫逃逸,变异可导致病毒的免疫学性状和机体特异性应答反应的改变，包括,S,基因、,Pre-C,基因、,C,基因的变异。,HBV,与原发性肝癌,携带者发生肝癌的危险性比正常人高,217,倍,X,基因编码的,X,蛋白有反式激活作用，可反式激活原癌基因等，从而影响细胞周期，促进细胞转化。,乙型肝炎的特点,我国约有40%-60%人群曾受到过,HBV,的感染,表现急性乙肝的仅占0.1%-1%,，,亚临床30%-75%，慢性乙肝1%-5%，乙肝病毒携带7%-20%),急性乙肝如治疗不彻底，10%患者可转为慢性乙肝,Lab diagnosis,HBsAg、,抗,HBs,HBeAg、,抗,HBe,抗,HBc（HBcAg）,HBV DNA,HBV,抗原、抗体检测（两对半）,HBV Antigen and Antibody detection,Antigens,surface antigen(HBsAg),e antigen(HBeAg),core antigen(HBcAg),Antibodies,surface antibody(anti-HBs),e antibody(anti-HBe),anti-HBc,Core IgM,Core IgG,HBsAg,presence of the virus,used as a general marker of,infection,.,is secreted in excess into the blood as 22 nm spheres and tubules.,Its presence in serum indicates that virus,replication,is occurring in the liver.,HBcAg,not detected in blood,HBeAg,secreted protein is shed in small amounts into the blood.,Its presence in serum indicates that a high level of viral replication is occurring in the liver.,indicates,active replication,of virus and therefore,infectiveness,.,anti-HBs,becomes detectable late in convalescence.,It remains detectable for life and is not found in chronic carriers.,used to document,recovery,and/or,immunity,to HBV,infection.,anti-HBe,antibodies to e and indicates,low infectivity,in a carrier and,probable recovery.,becomes detectable as viral replication falls.,virus no longer replicating.However,the patient can still be HBsAg,(+),which is made by integrated HBV.,anti-HBc,antibodies to the core can be either,IgM(acute),or,IgG(chronic),Core IgM,-rises early in infection,-,marker of,acute infection,Core IgG,-rises soon after IgM,and remains present for life in both chronic carriers and those who clear the infection.,-,marker of,past or chronic infection.,HBsAg,HBsAg,阳性见于急性肝炎、慢性肝炎或无症状携带者，是,HBV,感染的指标之一,，,是筛选献血员的必检指标,。,急性肝炎恢复后，一般在14个月内消失，若持续6个月以上者认为已向慢性肝炎转化。,无症状,HBV,携带者，可以长期,HBsAg,阳性。,抗-,HBs,是,HBV,的特异性中和抗体,，其出现表示,机体对乙肝病毒有免疫力,。,PreS1,和,PreS2,抗原,与病毒的,活动性复制,有关，为,病毒复制的指标,抗体,出现常见于,急性乙型肝炎恢复期的早期,，其检出提示病毒正在或已经被清除，预后良好,HBeAg,阳性提示,体内,HBV,在复制，有较强的传染性,，如转为阴性，表示病毒停止复制。,若持续阳性者则提示有发展成慢性肝炎的可能。,抗-,HBe,阳性,表示机体已获得一定的免疫力，,HBV,复制能力减弱，传染性降低,。,HBcAg,不易在血清中检出,，故不用于常规检测。,抗-,HBc,产生早，滴度高，持续时间长，几乎所有急性病例均可检出，,抗-,HBc IgM,阳性表示病毒复制，患者的血液有很强的传染性,。,The results analysis of HBV antigen-antibody detection,HBsAg,anti-HBs,HBeAg,anti-HBe,anti-HBc IgM,anti-HBc IgG,Interpretation,+,-,+,-,+,-,acute hepatitis,(high infectivity),+,-,+,-,-,+,chronic,hepatitis(high infectivity),+,-,-,-,-,-,HBV infection or,carrier,-,+,-,+,-,+,recovery hepatitis B(low infectivity),-,+,-,+,-,-,recovery hepatitis B(low infectivity),-,+,-,-,-,-,vaccine-type response,-,-,-,-,-,-,non-infection,non HBV response,no vaccination,病毒抗原抗体系统检测结果分析,HBsAg,HBeAg,抗-,HBs,抗-,HBe,抗-,HBc,结果分析,IgM,IgG,+,-,-,-,-,-,HBV,感染或无症状携带者,+,+,-,-,+,-,急性肝炎早期,（传染性强，“大三阳”）,+,-,-,+,-,+,急性感染趋向恢复（“小三阳”）,慢性乙型肝炎，无或低,HBV,复制,+,+,/-,-,-,+,+,急性乙型肝炎后期,-,-,+,-,+,乙型肝炎恢复期,-,-,-,-,-,+,既往感染,-,-,+,-,-,-,接种过疫苗,血清,HBV DNA,检测,应用核酸杂交法、常规,PCR,技术可直接检测血清中,HBV DNA。,检测血清中,HBV DNA,是病毒存在和复制的最可靠的指标，因此已被广泛应用于临床诊断和药物效果评价。,Prevention,控制传染源，切断传播途径（加强对供血源的筛选）,人工主动免疫：,疫苗（血源性、,基因工程,、,HBsAg,多肽疫苗),人工被动免疫：,高效价抗,-HBS,的人血清免疫球蛋白（,HBIg）,尚无特效疗法,Who,should,get,hepatitis B vaccine,?,1),Everyone 18 years of age and younger,2)Adults over 18 who are at risk,Adults at risk for HBV infection include:,-people who have more than one sex partner in 6 months,-men who have sex with other men,-sex contacts of infected people,-people who inject illegal drugs,-health care and public safety workers who might be exposed to infected blood or body fluids,-household contacts of persons with chronic HBV infection,-hemodialysis(,血液透析,)patients,Reducing the possibility of transmission,use a condom when you have sex,dont share drug needles with anyone,wear gloves if you have to touch anyones blood,dont use an infected persons toothbrush,razor,or anything else that could have blood on it,make sure any tattooing(,纹身,),or body piercing is done with clean tools,Hepatitis C virus,（,丙型肝炎病毒,）,Hepatitis C Virus,(+)RNA,Hepatitis C,Mild,chronic,Blood route,Anti-HCV antibodies,HCV RNA,No vaccine,生物学特性,C,区编码的核心蛋白，抗原性强，可诱导细胞免疫反应,E1/E2,区编码的包膜蛋白具有高度的变异性，引起免疫逃逸作用，是,HBV,感染慢性化的主要原因,Structure of HCV,HCV,电镜照片,HCV,的基因结构,Transfusion or transplant from infected donor,Injecting drug use,Hemodialysis,(,血液透析,),Accidental injuries with needles/sharps,Sexual/household exposure to anti-HCV-positive contact,Multiple sex partners,Birth to HCV-infected mother,Risk Factors Associated with Transmission of HCV,致病性与免疫性,传播途径似,HBV,极易慢性化,是引起输血后慢性肝炎和肝硬化的主要原因,无症状,HCV,携带者和慢性丙肝者多见,致病性与免疫性,HCV,感染与肝癌的发生也有密切关系。,致病机制与病毒的直接致病作用和免疫病理损伤有关,HCV,感染后不能诱导有效的免疫保护反应,Pathogenesis,persistent,chronic hepatitis,cirrhosis,hepatocellular carcinoma,acute hepatitis,15%,chronic persistent infection 70%,severe rapid progression to cirrhosis,15%,Lab diagnosis,HCV antibody,-generally used to diagnose hepatitis C infection.Not useful 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,-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.,Treatment,Interferon,-may be considered for patients with chronic active hepatitis.The response rate is around 50%but 50%of responders will relapse,(,复发,),upon withdrawal of treatment.,Ribavirin,(,利巴韦林,),-there is less experience with ribavirin than interferon.However,recent studies suggest that a combination of interferon and ribavirin is more effective than interferon alone.,Screening of blood,organ,tissue donors,High-risk behavior modification,Blood and body fluid precautions,Prevention of Hepatitis C,Prevention,对献血员进行抗,-HCV,检测，对血制品进行,HCV,检测,因,HCV,免疫原性不强及变异，目前尚无可用疫苗,缺乏特效药物，,IFN-,是目前最常用抗病毒制剂,A,defective virus,need help from,HBV,The agent consists of a particle 35 nm in diameter consisting of the delta antigen surrounded by an outer coat of,HBsAg,.,The genome of the virus is very small and consists of a single-stranded RNA,Acute self-limited infection,fulminant,liver failure,chronic liver infection,Delta antigen,and antibody,Hepatitis D Virus,第四节 丁型肝炎病毒,（,HDV）,HDV,是一种缺陷病毒,由,HBsAg,构成其外壳，形成35-37,nm,颗粒,颗粒内部由,HDV RNA,和,HDAg,组成,单负链环状,RNA,Hepatitis Delta Virion,HDV,的结构,Rizzetto,于1977年首先发现，又称,抗原,35-37,nm,球形颗粒；,1.7,Kb-ssRNA,含9个,ORF,Consequences of hepatitis B and delta virus infection,Consequences of deltavirus infection.,Deltavirus(d)requires the presence of hepatitis B virus(HBV)infection.Superinfection of a person already infected with HBV(carrier)causes more rapid,severe progression than co-infection(,shorter arrow,).,Pathogenesis and immunity,HDV,感染后可表现为急性肝炎、慢性肝炎和无症状携带者。,其感染方式有两种：一是,联合感染,，二是,重叠感染,。,HDV,可刺激机体产生特异性抗体，但这些抗体不是中和抗体，不能清除病毒。,HDV,与,HBV,有相同的传播途径。,Lab diagnosis and prevention,诊断为检测抗-,HD,HDV-RNA,防治原则似,HBV,Hepatitis E Virus,戊型肝炎病毒,球形，无包膜，直径3234,nm,分类尚未最后确定,单正链,RNA,，3,个,ORF,体外培养困难,至少有,8,个基因型,Hepatitis E Virus,Hepatitis E,acute infection,Affects,young adults,particularly in pregnant women,Symptoms:Jaundice,anorexia,enlarged tender liver,abdominal pain and tenderness,nausea,vomiting,fever,Fecal-oral route,especially contaminated water,Hepatitis E Virus,Pathogenesis,主要经粪口途径传播,由胆汁经粪便排出体外,对肝细胞的直接损伤及免疫病理作用,多表现为急性戊型肝炎,孕妇感染病情常较重，常致流产或死胎,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,Weeks after exposure,Titer,戊型肝炎的特点,与甲型肝炎相比，患者黄疸前期症状重，病程持续时间较长，病死率较高，特别是孕妇感染,HEV,后。青壮年是,HEV,最喜欢攻击的人群。,戊型肝炎分两种：“流行性”多发生在雨季和洪水后,“,散发性”在秋冬季呈现高峰。,传染性强的时间在患者将要出现症状前(潜伏末期)至发病初期，患者的隔离期为起病后3周。,尚末发现有2次发病者。,Lab diagnosis and Prevention,检测,HEV：EM,或,IEM,检测抗-,HEV IgM,或,IgG,检测,HEV RNA,预防与甲肝类似,无有效疫苗和特异性抗病毒药物,Prevention and Control Measures for Travelers to HEV-Endemic Regions,Avoid drinking water,(and beverages with ice)of unknown purity,uncooked shellfish,and uncooked fruit/vegetables not peeled or prepared by traveler.,IG prepared from donors in Western countries does not prevent infection.,Unknown efficacy of IG prepared from donors in endemic areas.,Vaccine?,第六节 肝炎相关病毒,庚型肝炎病毒,，生物学性状与,HCV,相似。传播途径与,HBV,和,HCV,相似，主要经输血等非肠道途径传播，也存在母,-,婴传播及静脉注射吸毒和医源性传播。常与,HBV,或,HCV,合并感染，单独感染时临床症状不明显，一