人卫微生物Chapter疱疹病毒

Chapter 31 Herpesviruses,人疱疹病毒,1,Herpesviruses,The name herpes comes from the Latin herpes which, in turn, comes from the Greek word herpein which means to creep (爬行).This reflects the creeping or spreading nature of the skin lesions caused by many herpesvirus types.,2,After the primary infection, herpesviruses establish latency in the infected host.Once a patient was infected by herpes virus, the infection will remain for life.Intermittently, the latent genome can become activated, in response to various stimulus, to produce infectious virus particles.Herpesviruses are a leading cause of human viral disease, second only to influenza and cold viruses.Nearly 100 kinds of Herpesviruses have been isolated and there are 8 known human Herpesviruses.,General properties of herpesviridae,3,Herpesviridae- Infection and Disease,4,Biological classification,Herpesviruses are classified into three groups based upon of tissue tropism（趋向）, pathogenicity and behavior herpesviruses herpesviruses herpesviruses,5, herpesviruses,Fast replicatingVariable host rangeTypically destroy host cell (cytolytic)Latency established in sensory ganglia（神经节）Herpes Simplex（单纯性疱疹） virus-1 and 2 (HSV-1/HSV-2)Varicella-Zoster（水痘带状疱疹）virus (VZV),6, herpesviruses,Slowly replicatingRestricted host rangeInfected cells enlarge Latency established in multiple tissues (secretory glands, kidneys)Cytomegalovirus (CMV)巨细胞病毒Human Herpesvirus-6 and 7 (HHV-6/HHV-7),7,herpesviruses,Replicate poorlyHighly restricted host rangeLatency established in lymphoid tissue (T-cell or B-cell specific)Epstein-Barr Virus (EBV), a B-cell transforming virusHuman Herpesvirus-8 (HHV-8, KSHV),8,All of them are morphologically similar: lipid envelope with glycoprotein spikes 100-nm icosahedral capsid internal core of linear, double-stranded DNA,General structure,9,The Herpesviridae family comprises large, DNA-containing enveloped viruses.,General structure,10,Herpes virus Particle,HSV-2 virus particle. All herpes virus have identical morphology and cannot be distinguished from each other under electron microscopy.,11,HHV的特性：,包膜：球形,150-200 nm 核衣壳：立体对称基因组：dsDNA，编码多种蛋白和酶增殖：核内复制出芽，融合成多核巨细胞感染类型：溶细胞性感染 潜伏感染 细胞永生化免疫：细胞免疫控制HHV感染,12,Herpes simplex virus, HSV;HHV-1,第一节 单纯疱疹病毒,13,Herpes Simplex Virus(HSV),14,Biological characterization,Double stranded DNA enveloped virus There are two types with very similar characteristics. HSV-1 (HHV-1) HSV-2 (HHV-2)The genome of HSV-1 and HSV-2 share 50% homology.,15,血清型：HSV-1和HSV-2 基因组：150 kb, 编码70多种蛋白 与病毒增殖有关：DNA聚合酶、TK等 与细胞相互作用有关： 粘附性糖蛋白：gB、gC、gD和gH 融合蛋白：gB等。,16,免疫逃逸：gC，gE/gL复合物；与结构有关： 衣壳蛋白 包膜糖蛋白：gC，gL，gE等 与分型有关： 血清型：gG（型特异性糖蛋白） gG-1代表HSV-1，gG-2为HSV-2,17,glycoprotein B (gpB) spikesvisible in membrane,Herpesviridae,18,Pathogenesis,Human is the only natural host for HSV.HSV-1 is usually spread mouth to mouth or transfer virus to the hands.HSV-2 is normally spread sexually.An infant can be infected at birth by a genitally（性）-infected mother or in utero ( 子宫).,19,性接触；垂直传播疱疹液（手，眼，皮肤）传播,传播途径,密切接触传播：唾液、阴道分泌物， 疱疹液，接吻，共用 杯子，牙刷等,20,HSV感染较普遍 密切接触和性接触 经粘膜和破损皮肤上皮细胞内复制，水疱浆液充满病毒颗粒，细胞碎片，基底部多核巨细胞；神经细胞则为潜伏感染。,皮肤损伤性水疱,21,Primary infection,First infect the mucous membranes and epithelia.Generally HSV-1 causes infection above the waist and HSV-2 below the waist.Both can also persistently infect macrophages and lymphocytes.The typical lesion（损害 ）is the vesicle (水疱),22,HSV-1 usually occurs around the mouth. The blister-like sores are commonly called cold sores.,23,HSV-2 usually occurs in the genital area (shaded).,24,原发感染 表现：粘膜与皮肤的局部疱疹 HSV-1：腰以上感染为主,唇疱疹,角膜结膜炎,龈口炎,25,HSV-2：腰以下及生殖器感染为主 生殖系统疱疹、新生儿疱疹等,26,Latent infection,During the primary infection, HSV spreads locally and a short-lived viremia occurs, whereby the virus is disseminated in the body. Spread to the craniospinal全脑全脊髓 ganglia.The virus then establishes latency in the craniospinal ganglia.HSV-1: trigeminal ganglia (三叉神经节) and superior cervical ganglia (颈上神经节)HSV-2: sacral ganglia (骶神经节),27,感觉神经节,HSV-1: 三叉神经节和颈上神经节HSV-2: 骶神经节,潜伏的HSV不复制，对抗病毒药物不敏感,潜伏感染,原发感染后, HSV由感觉神经,28,Reactivation and Recurrence,Several agents may trigger （引发） recurrence. emotional stress, exposure to strong sunlight, fever, a weakened immune system, etc.The virus can travels back down the nerve axon（轴突） and arrives at the mucosa that was initially infected.Vesicles （水泡） containing infectious virus are formed on the mucosa and the virus spreads.Recurrent infections are usually less pronounced than the primary infection and resolve more rapidly.,29,Pathway of HSV Infection,HSV entersthe body,HSV lies dormantin the nerves,HSV is reactivated,causing another outbreak,HSV enters body through a break in the skin or mucous membranes,After initial infection, HSV settles in the sacral ganglia,HSV travels alongthe nerves, back to theskin to form new blisters,30,复发性感染,非特异性刺激：发热、月经、感染等,感染粘膜或皮肤上皮细胞,免疫记忆反应,病程短, 组织损伤轻, 感染更局限,激活潜伏病毒沿感觉神经纤维下行到末梢（原发部位）,31,Clinical Features,HSV-1 infectionHSV-2 infectionNeonatal (新生的) HSV infection,32,HSV-1 Infection,Acute Gingivostomatitis (龈口炎)Commonest manifestation of primary herpetic infection. 1 - 8 mm ulcers with necrotic bases are presentNeck glands are commonly enlarged accompanied by fever. Usually a self limiting disease which lasts around 13 days. Herpes labialis (cold sore, fever blisters) (唇疱疹)It is a recurrence of oral HSV.45% of orally infected individuals will experience reactivationProdrome of tingling, warmth or itching usually heralds recurrenceAbout 12 hours later, redness, then papules and then vesicles,33,Acute Gingivostomatitis (龈口炎),34,cold sore,35,HSV-1 Infection,Ocular HerpesHSV causes a broad spectrum of ocular disease, ranging from mild superficial lesions involving the external eye, to severe sight-threatening diseases of the inner eye. Diseases caused include:Primary HSV keratitis dendritic ulcersRecurrent HSV keratitisHSV conjunctivitis Iridocyclitis, chorioretinitis and cataract,36,Ocular Herpes,37,Herpes Simplex Encephalitisone of the most serious complications of herpes simplex disease. There are two forms: -Neonatal: there is global involvement and the mortality rate approaches 100% -Focal disease: the temporal lobe is most commonly affected and the mortality rate is high (70%) without treatment.It is of utmost importance to make a diagnosis early to limit mortality.,HSV-1 Infection,38,Genital HerpesGenital lesions may be primary, recurrent or initial. Many sites can be involved which includes the penis, vagina, cervix, anus, vulva, bladder, the sacral nerve routes, the spinal and the meninges. The lesions of genital herpes are particularly prone to secondary bacterial infection eg. Staphylococcus aureus , Streptococcus, Trichomonas and Candida Albicans. Dysuria is a common complaint, in severe cases, there may be urinary retention. Local sensory nerves may be involved leading to the development of a radiculitis. A mild meningitis may be present.,HSV-2 Infection,39,Neonatal HSV infection,HSV-2 mostly, HSV-1 15-30%The baby is usually infected perinatally during passage through the birth canal. When dissemination occurs, the organs most commonly involved are the liver, adrenals and the brain.When the brain is involved, the prognosis is particularly severe. The encephalitis is global and of such severity that the brain may be liquefied.A large proportion of survivors of neonatal HSV infection have residual disabilities.,40,Infants may acquire congenital herpes from a mother with an active herpes infection at the time of birth.,41,免疫IFN和NK细胞：限制原发感染发展中和抗体：阻断病毒扩散及潜伏感染细胞免疫：控制和消除HSV感染,42,Laboratory Diagnosis,Direct DetectionElectron microscopy of vesicle fluid - rapid result but cannot distinguish between HSV and VZVImmunofluorescence of skin scrappings - can distinguish between HSV and VZVPCR - now used routinely for the diagnosis of herpes simple encephalitisVirus Isolation HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available.SerologyNot that useful in the acute phase because it takes 1-2 weeks before antibodies appear after infection. Used to document to recent infection.,43,检测核酸 PCR或原位杂交检测HSV的DNA检测抗原 刮取疱疹基底部组织 荧光素或酶标记抗体染色 检查细胞内疱疹病毒抗原分离病毒 标本：水疱液、唾液或CSF 细胞：BHK-21，Vero CPE：细胞肿胀；融合细胞；包涵体,44,Treatment,acyclovir - nucleoside analog drugPatients with genital herpes should avoid intercourse when they have the prodromal itching symptoms or an active lesion.,45,Varicella zoster virus（VZV）,第二节 水痘-带状疱疹病毒,46,Varicella-Zoster Virus,(also known as Herpes Zoster Virus, Human Herpes Virus-3),47,Alphaherpesvirus subfamily of herpesvirusesDouble stranded DNA enveloped virusOne antigenic serotype only Some cross reaction with HSV,Biological characterization,48,与HSV相似： 潜伏神经细胞，引起复发感染 细胞免疫限制和防止重症水痘 皮肤损伤以水疱为特征 编码TK等, 对抗病毒药物敏感与HSV不同： 呼吸道感染 通过病毒血症播散至皮肤,生物学性状,49,Varicella-Zoster Virus (VZV),Initial infection usually in childhood with Varicella virus (HHV-3)- Chicken Pox (水痘)It is spread by respiratory aerosols or direct contact with lesionsThe virus establishes latency within the dorsal背部的 root ganglia（脊髓后根神经节）Years or decades later, the virus (Herpes zoster) may reactivate - Shingles (带状疱疹),50,chicken-pox (Varicella),Each spot starts as a 2-4 mm diameter red papule which develops an irregular outline (rose petal) as a small vesicle appears on the surface. This dew drop on a rose petal appearance is the characteristic of chickenpox.,51,Zoster means girdle腰带 , from the characteristic rash that forms a belt around the thorax胸 .,Herpes Zoster (Shingles),52,Herpes Zoster (Shingles),Herpes Zoster mainly affect a single dermatome皮片 of the skin. It may occur at any age but the vast majority of patients are more than 50 years of age. The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment. Herpes zoster affecting the eye and face may pose great problems.As with varicella, herpes zoster in a far greater problem in immunocompromised patients in whom the reactivation occurs earlier in life and multiple attacks occur as well as complications.,53,Shingles,54,水痘和带状疱疹,致病性与免疫性,原发感染,复发性感染,55,原发感染和潜伏感染,56,Pathogenesis,57,How the VZV causes shingles and postherpetic neuralgia,58,复发性感染,59,Laboratory Diagnosis,The clinical presentations of varicella or zoster are so characteristic that laboratory confirmation is rarely required. Laboratory diagnosis is required only for atypical presentations, particularly in the immunocompromised.Virus Isolation - rarely carried out as it requires 2-3 weeks for results.Direct detection - electron microscopy may be used for vesicle fluids but cannot distinguish between HSV and VZV. Immunofluorescense on skin scrappings can distinguish between the two.Serology - the presence of VZV IgG is indicative of past infection and immunity. The presence of IgM is indicative of recent primary infection.,60,Prevention,A live attenuated vaccine is available and is now recommended for routine use after 12 months of age in healthy children. Where urgent protection is needed, passive immunization should be given. Zoster immunoglobulin (ZIG) is the preparation of choice but it is very expensive. Where ZIG is not available, HNIG( human normal immunoglobulin) should be given instead.,61,Treatment,Uncomplicated varicella is a self-limited disease and requires no specific treatment. However, acyclovir had been shown to accelerate the resolution of the disease and is prescribed by some doctors.Acyclovir should be given promptly to immunocompromised individuals with varicella infection and normal individuals with serious complications such as pneumonia and encephalitis.Herpes zoster in a healthy individual is not normally a cause for concern. The main problem is the management of the postherpetic neuralgia.,62,诊断：似HSV治疗：无环鸟苷 IFN：限制疾病、缓解局部症状预防：减毒活疫苗,微生物学检查法与防治,63,Human cytomegalovirus（HCMV）,第三节 人巨细胞病毒,64,Cytomegalovirus,largest genome of all herpes viruses only to replicate in human cells causes no symptoms in children and at most mild disease in adults,65,形态结构：与HSV极相似；感染的细胞肿大，并具有巨大的核内包涵体，故名；核内包涵体呈“猫头鹰眼”状宿主范围： 较窄，不感染其它动 物；仅成纤维细胞中 增殖。,生物学性状,66,HCMV传播增殖: 各种腔管道上皮细胞内 血、唾液、乳液、尿、阴道分泌物等传播: 通过胎盘至胎儿、产道至新生儿 乳液和唾液至儿童 输血和器官移植传播 接触性感染，包括性接触,致病性与免疫性,67,原发感染 (primary infection) 儿童和成人通常隐性感染；单核细胞增多症潜伏感染 (latent infection) 多数长期带毒 潜伏部位：唾液腺、乳腺、肾、白细胞等长期或间歇地自唾液、乳汁、尿液、精液或宫颈分泌物中排出病毒复发性感染 (reactivation and recurrence) 器官移植、AIDS、白血病和淋巴瘤等；长期用免疫抑制剂、激活潜伏病毒；引起肺炎、结肠炎和脑膜炎等。,68,先天性疾病：通过胎盘引起胎儿感染、死胎或先天性疾病巨细胞包涵体病：肝脾肿大、黄疸、溶血性 贫血等；神经系统损伤：耳聋和智力低下等,69,HE stain of lung section showing nuclear inclusions with the appearance of an owls eye. The inclusion is surrounded by a clear halo that extends to the nuclear membrane. CMV infection can occur without the typical cytomegalic cells.,70,Pathogenesis and symptomatology,71,Transmission,Intrauterine (子宫内) maternal viraemia and placental infection Perinatal (围产期) infected genital secretions or breast milkPostnatal (出生后的) sexually transmitted, transplanted organs, blood transfusions,72,Pathogenesis,Once infected, the virus remains in the person for life and maybe reactivated from time to time, especially in immunocompromised individuals.Eventually CMV attains a latent state and persistent infection within T-cells, endothelial cells and monocyte-derived macrophages.,73,Clinical Features,Congenital infection The most common cause of congenital infection 95% of infected babies are asymptomatic, 5% may result in cytomegalic inclusion disease with poor prognosis Perinatal infection - usually asymptomaticPostnatal infection - usually asymptomatic. Immunocompromised patients such as transplant recipients and AIDS patients are prone to severe CMV disease such as pneumonitis, retinitis, colitis, and encephalopathy.,74,The classical presentation of cytomegalic inclusion disease is IUGR( intrauterine growth retardation), jaundice, hepatosplenomegaly, thrombocytopenia and encephalitis.,75,Cytomegalovirus can cause serious infections in people with impaired immunity. The infection may result in pneumonia, gastroenteritis, retinitis or encephalitis.,76,Laboratory Diagnosis,Direct detection Virus IsolationSerology,77,DEAFF test for CMV,DEAFF( Detection of Early Antigen Fluorescent Foci),78,细胞培养：成纤维细胞中增殖，生长慢，CPE需26周,ELISA：HCMV-IgM；近期感染；胎儿感染,HCMV CPE 包涵体,微生物学检查法,79,Prevention,No licensed vaccine is available.,80,Treatment,Congenital infections - it is not usually possible to detect congenital infection unless the mother has symptoms of primary infection. If so, then the mother should be told of the chances of her baby having cytomegalic inclusion disease and perhaps offered the choice of an abortion.Perinatal and postnatal infection - it is usually not necessary to treat such patients.Immunocompromised patients - it is necessary to make a diagnosis of CMV infection early and give prompt antiviral therapy. Anti-CMV agents in current use are ganciclovir, forscarnet, and cidofovir.,81,第四节 EB病毒,Epstein-Barr virus，EBV,82,Epstein-Barr Virus,83,Belong to the gammaherpesvirus subfamily of herpesviruses.Membrane is derived by budding of immature particles through cell membrane and is required for infectivity.Genome is a linear double stranded DNA molecule.The viral genome does not normally integrate into the cellular DNA but forms circular episomes which reside in the nucleus.,Biological characterization,84,形态结构类似HSV,生物学性状,85,增殖性感染产生的抗原：早期抗原（early antigen，EA）： DNA聚合酶活性, 表示EBV增殖 EA抗体：早期抗体, 持续几个月 表示近期感染,86,衣壳抗原（viral capsid antigen，VCA）： 结构蛋白，存在细胞质和细胞核 VCA-IgM出现早，消失快 VCA-IgG出现晚，持续几年EBV膜抗原（membrane antigen, MA）： 在细胞表面，属包膜糖蛋白 MA-IgM表示近期感染 MA-IgG可持续存在,87,潜伏感染 EBV感染B细胞或上皮细胞 潜伏感染细胞含EBV基因组 (游离或整合)选择性表达潜伏期抗原，刺激B细胞增生或永生化,88,EBV潜伏期抗原核抗原（EB nuclear antigen，EBNA） B细胞核内，为DNA结合蛋白 维持EBV基因组在感染细胞内 感染细胞逃避CTL杀伤 与细胞永生化有关 EBNA抗体：感染晚期, 持续存在,潜伏膜蛋白（latent membrane protein, LMP） 在B细胞表面, 致癌蛋白 改变细胞功能, 抑制细胞凋亡 阻止潜伏病毒激活功能,89,Pathogenesis,Spread by close contact and blood transfusion.Initially replicated in pharyngeal epithelial cells, shed into the saliva and is taken up by B lymphocytes.Enters B lymphocytes by binding to surface receptor CD21Infected B lymphocytes enter the blood and spread the infection throughout the body.B lymphocytes are only semi-permissive for replication of the virus and infection may either be latent or the cells may be transformed by the virus.Immortalization and proliferation of the cells are associated with the expression of the viral genome. Furthermore, EB virus is a potent polyclonal activator of B lymphocytes which may generate heterophile antibodies.The infected B lymphocytes may stimulate the proliferation of T lymphocytes and cause atypical lymphocytosis.,90,Clinical Features,The etiological agent of Infectious Mononucleosis (传染性单核细胞增多症)The major biological cofactor contributing to a number of human cancers includingB-cell neoplasm( Burkitts lymphoma, Hodgkins disease, Immunoblast lymphoma )T cell lymphomaSome epithelial tumors ( Nasopharyngeal carcinoma (鼻咽癌), gastric carcinomas (胃癌),91,Infectious mononucleosis,92,Burkitt淋巴瘤 96100与EBV相关 瘤细胞含EBV、DNA和EBNA,致病性与免疫性,Burkitts lymphoma,93,鼻咽癌：广东、湖南等地,血清：高效价抗VCA、 EA IgG及IgM 抗体升高常在肿瘤之前癌：含EBNA和LMP PCR查到EBV基因组 鼻咽癌治疗后好转， 抗体滴度下降,94,传染性单核细胞增多症,唾液, 接吻, 共用杯子和牙刷等,口咽部上皮细胞增殖,感染淋巴组织中的B细胞,入血,全身性EBV感染表现单核细胞增多,EBV,95,Laboratory Diagnosis,Acute EBV infection is usually made by the heterophil antibody test and/or detection of anti-EBV Virus Capsid Antigen (VCA) IgM.Cases of Burkitts lymphoma should be diagnosed by histology. The tumour can be stained with antibodies to lambda light chains which should reveal a monoclonal tumour of B-cell origin. In over 90% of cases, the cells express IgM at the cell surface. Cases of NPC should be diagnosed by histology.The determination of the titer of anti-EBV VCA IgA in screening for early lesions of NPC and also for monitoring treatment.A patient with non-specific ENT (ear, nose, and throat) symptoms who have elevated titers of EBV IgA should be given a thorough examination.,96,Vaccination,A vaccine against EBV which prevents primary EBV infection