病原微生物學(xué)教學(xué)課件：16-Flavivirus

1、Flavivirus病原微生物 Pathogen BiologyFlaviviridaePestivirusesFlavivirusesHepaciviridaeHepatitis C virusBVD, Hog cholera, Border diseaseYellow feverJapanese encephalitisSt. Louis encephalitisDengueWest Nile virus(arthropods, biological vectors)Togaviruses and FlavivirusesnTogaviruses Human PathogenspAlpha

2、virus ArbovirusespRubivirus Rubella viruspArterivirus NonenFlaviviruses ArbovirusespHepaciviridae HCVpPestivirus Nonepall Flaviviruses share a common antigennEnvelope glycoproteinnHemagglutininp65 different types of flaviviruspone-third human pathogenspseveral antigenic subgroupsnmite bornentick bor

3、neFlaviviruses: ClassificationpReplication in cytoplasmpvirions assembled in golgi and Smooth ERpTransported by vesicles to plasma membranepVirus RNA acts as mRNAncapped, no poly A tailnmRNA - proteinnmRNA- antisense RNAnAntisense RNA - sense RNA FlavivirusespEncephalitisnSt. louis encelphalitis, Ja

4、panese encephalitis, Powassan, tick borne encephalitispFebrile illness with rashnDengue viruspHemorrhagic fevernKyasanur Forest viruspHemorrhagic fever with hepatitisnYellow fever virusFlaviviruses: Clinical manifestationsArthropod VectorsAedes Aegyti （伊蚊）Assorted Ticks （虱、蜱）Culex Mosquito （庫蚊）Phleb

5、otmine Sandfly （吸血白蛉）Transmissionphuman-arthropod-humanpanimal-arthropod-humanpmixHuman-Arthropod-HumanDengue Reservoir may be in either man or arthropod vectorIn the latter transovarial transmission may take placeAnimal-Arthropod-HumanJapanese encephalitisThe reservoir is in an animal, The virus is

6、 maintained in nature in a transmission cycle involving the arthropod vector and animalMan becomes infected incidentallyJapanese EncephalitisBackgroundp1870s: Japann“ “Summer encephalitis” ” epidemicsp1924: Great epidemic in Japann6,125 human cases; 3,797 deathsp1934: Reproduce the disease in monkey

7、p1935: First isolatednBrain from a fatal human encephalitis casep1938: Isolated from Culex tritaeniorhynchusBackgroundp1940-1978nDisease spread with epidemics in China, Korea, and Indiap1983: Immunization in South KoreanStarted as early as age 3nEndemic areas started earlierp1983-1987: Vaccine avail

8、able in U.S. on investigational basisPathogen-JEV and FlavivirusespJEV is one of 66 flavivirusespbelongs to the Japanese encephalitis serocomplex, which is composed of several flavivirusesnAlfuy, Koutango, Kokobera, Kunjin, Murray Valley encephalitis, Japanese encephalitis, Stratford, Usutu, West Ni

9、le, and St. Louis encephalitis. nUsutu virus, an African mosquito-borne flavivirus, emerged in 2002 and since then has appeared in many European countries, presenting even further surveillance and transmission challenges. Vazquez A, et al. Euro Surveill. 2011;16:Non-segmented, single stranded, posit

10、ive sense RNA viruses related to hepaciviruses and GB virusesSpherical, 40-60 nm in diameterLipid envelope covered with surface projections, especially E, pre-M and M proteinsWest NileKunjinJapanese encephalitisMurray Valley encephalitisSt. Louis encephalitisdengue-1dengue-3dengue-2dengue-4yellow fe

11、verCentral European encephalitisFar Eastern encephalitisPowassanDakar batJapaneseencephalitisdenguenonetick-borneencephalitisnoneXIVXIIXVIIIVIIImosquito-bornetick-borneno vectorvirusserocomplexcladeclusterFlavivirus genus. The dendrogram on the left shows the relationships of selected flaviviruses b

12、ased on a recent phylogenetic analysis. The serologic and phylogenetic classifications of these viruses are indicated to the right.Fields Virology, 4th Edition. Philadelphia, Lippincott-Williams & Wilkins. 2001, p 995Flaviviruses (some), mosquito-borne S. Asia, Japan, Korea, China, India, Philip

13、pines, etc. Vaccine Australia, New Guinea None Africa, Middle East, southern France, Former Soviet Union, India, Indonesia, US Screening blood and blood products for the virus North and South America NoneJapanese encephalitisMurray Valley encephalitisWest Nile VirusencephalitisSt. Louis encephalitis

14、JEV Genotypic VariantsType IChina, India, Japan, Nepal, Sri Lanka, Taiwan, and VietnamType IICambodia and N. ThailandType IIIIndonesia, Malaysia, and S. ThailandVaccine targetType IVIndonesian and Malaysian regionsJEVGeographic distribution of medically important flavivirusestransmissionA, Regions w

15、ith yellow fever viral transmission. B, Regions with Japanese encephalitis virus transmission. C, Countries with West Nile virus transmission. D, Countries with tick-borne encephalitis transmission Strauss, Viruses and Human Disease. San Diego, Academic Press, 2002All flaviviruses would appear simil

16、ar to DengueEpidemiologyOnly distributes in AsiaPrimarily a disease of rural AsiaVector mosquitoes proliferate in close association with birds and pigsBirds and pigs are the major amplifying hostsMany other mammals and reptiles infected as well, long term viremia documented in bats, othersCulex trit

17、aeniorhynchus the principal vector but many other mosquitoes are competent and can transmitC. pipiensC. quinquefasciatusSpecies of Aedes, AnophelesVirus overwinters in mosquitoes as well as vertical transmissionTraditional seasonal spread (spring/summer) heavily impacted by rice paddy floodingA sing

18、le rice paddy can produce 30,000 mosquitoes per dayIncidence and PrevalencepCommonest cause of encephalitis in AsiapIn hyperendemic areas half of all cases occur in children under 4 years of age, nearly all before age 10pNearly 100% seroprevalence by adulthood in heavily infected areaspEpidemic and

19、endemic formsp20,000 cases and 6,000 deaths annually a gross underestimatepMathematical modeling predicts 175,000 annual cases, 43,750 fatalities, 78,750 with disabilityIncidence and PrevalencepRatio of apparent to inapparent infection ranges from 1:250 in susceptible Asians to 1:63 in adult US mari

20、nes, 1:18 in Torres strait outbreakpRatio affected by age, virulence of the strain of virus, cross protective immunity from other flaviviruses (dengue)pRisk to travelers 1 case per 50,000 months of exposureEpidemiologypSymptomatic Japanese encephalitis has a male-to-female ratio of 1.5:1. pSerologic

21、 evidence of JEV infection in endemic rural areas is found in nearly all inhabitants by early adulthood. pMost symptomatic infections in endemic areas occur in young children (aged 2-10 y) and elderly people. pIn nonendemic areas, JEV infection has no age predilection. EpidemiologypOccurrence in the

22、 United nIn the United States, Japanese encephalitis develops mostly among military personnel, expatriates, and, rarely, returning travelers. From 1978-1993, 12 cases occurred in the United States. The risk of symptomatic infection among travelers is estimated to be 1 case per 150,000 person-months

23、in an endemic area. Outbreaks are rare in the US territories of Guam and SaipanEpidemiologypInternational occurrence nJapanese encephalitis is a seasonal disease, mostly occurring from June to September. nGlobally, more than 45,000 cases are reported each year pIn Chinan8090% case all focus on July,

24、 August, SeptembernSouth China: June JulynNorth China: July AugustnNE: August SeptembernShanghai: late July early AugustTransmissionpVector-bornepEnzootic cyclenMosquitoes: Culex speciespCulex tritaeniorhychusnReservoir/amplifying hostspPigs, bats, Ardeid (wading) birdspPossibly reptiles and amphibi

25、ansnIncidental hostspHorses, humans, othersCenter for Food Security and Public Health, Iowa State University, 2011Mode of TransmissionPlotkin, Orenstein. Vaccines, 4th ed. P 928Morbidity/MortalitypSwinenMortality high in piglets; rare in adultspEquinenMortality rare (5%) pHumansnMortality: 5 to 40%n

26、Serious neurologic sequelae: 45 to 70%Subcutaneous injectionRegional lymph nodesExtraneural Tissues Connective tissue Striated muscle Pancreas Adrenal Smooth muscleEfferent lymphaticsThoracic ductPlasma ViremiaReticuloendothelialcell clearanceHumoral antibodyOlfactory epitheliumVascular endotheliumN

27、eural ParenchymaNeurons, Glia(?)CNS antibodylymphocytes, macrophageCellular dysfunction Cellular lysisInflammation?PathogenesisModified based on Fields Virology, Vol 1, Fourth Edition. Lippincott-Williams & Wilkins , pp 1057, 2001BBBSubclinical formMild formCNS Japanese EncephalitisLight typeMed

28、ium typeSevere typeClinical Manifestationsp35,000-50,000 cases annuallypLess than 1 case/year in U.S.nMilitary, travelerspMost asymptomatic or mild signsp1 per 250 JEV infections results in symptomatic disease pChildren and elderlynHighest risk for severe diseaseClinical ManifestationpHistory of mos

29、quito exposure in an endemic areapIncubation period average: 6-8 days, with a range of 5-15 dayspProdromal period: several daysnFever 39-40nHeadachenNauseanDiarrheanVomitingnMyalgiaClinical ManifestationspIncubation 6-16 days. Spectrum from mild febrile headache to severe encephalitispHeadache, feve

30、r, nausea, vomiting, drowsiness. Abdominal pain and diarrhea common in childrenpProgression over several days to severe diseasenDull, mask-like faciesnMuscular rigiditynCranial nerve palsiesnTremulous eye and extremity muscle movementsnGeneralized and localized paresis, incoordination, pathologic re

31、flexespSeizures frequent in children, 40, coma, persistently twitch, might have failure ofrespiratory, might have sequelaepFulminate type nTmax 40 high fever, deep coma, intractable seizure, centrally respiratory failure during very short period, severe sequelae for survivalsTypeTemperature（ （） ）Lev

32、el of consciousnessseizureMeningealIrritation/Pathological reflexRespiratory failureNeuropsychiatric sequelaeLight38-39arousenolightnonoMild39-40lethargy/delirium/obtundationoccasionallyobviousnonoSevere 40Studor/comafrequent/persistentobviousmightmightFulminate 40Deep comaintractableobviousrapidoft

33、enClinical ManifestationClinical Manifestation: SeverepAcute encephalitis nHeadache, high fever, stiff neck, stupornMay progress to paralysis, seizures, convulsions, coma, and deathpNeuropsychiatric sequelaen45 to 70% of survivorspIn utero infection possiblenAbortion of fetusPost Mortem LesionspPan-

34、encephalitispInfected neurons throughout CNSpOccasional microscopic necrotic focipThalamus generally severely affectedSingh, AJNR 2001;22:1131Magnetic Resonance Abnormalities in Severe JEKalita, AJNR 2000;21:1978Substantia nigra involvementBilateral asymmetric thalamic hyperintensity Chinese Medical

35、 Journal 1997;60:10514 days after onset. Thalamicand basal ganglia involvementBasal GangliaThalamiMidbrain involvement220 days post onset. Hyperintenselesions at globus pallidus bilaterallyMRI in Flaviviral EncephalitisSolomon, NEJM 2004T2-Weighted Images showing Thalamic enhancement and swelling in

36、 :(A) Japanese encephalitis (B) West Nile Encephalitis (C) Murray Valley EncephalitisJapaneseencephalitisWest NileencephalitisMurray ValleyencephalitisSummary on Clinical ManifestationpSpecial seasonal onset, endemic areapHistory of mosquito exposure in an endemic areapAbsent or partial vaccination

37、pquick onset, headache, high fever, variable CNS symtoms including: nneck stiffness, stupor, disorientation, coma, tremors, occasional convulsions (especially in infants) and spastic (but rarely flaccid) paralysisDiagnosispHistory of mosquito exposure in an endemic area.pClinical diagnosis is unreli

38、ablepIgM capture EIA the most widely used methodpCSF or serum positive in 75% of patients within 4 days of symptom onset, nearly 100% within 7 dayspBoth serum and CSF should be tested to maximize sensitivityDiagnosispLaboratory confirmation requiredpSuspected casenAntibody titer: HI, IFA, CF, ELISAn

39、JE-specific IgM in serum or CSFpDefinitive casenVirus isolation: CSF, brainDiagnosisCase Definition - Suspected casenAcute onset of fever ( 7 days)nchange in mental status With/ withoutnNew onset of seizures (excluding febrile seizures)n (Other early clinical findings - may include irritability, som

40、nolence or abnormal behavior greater than that seen with usual febrile illness)Case ClassificationLaboratory-Confirmed caseSuspected case with any one of the following markers:n Presence of Ig M antibody in serum and/ or CSFn Four fold difference in Ig G antibody titer in paired seran Virus isolatio

41、n from brain tissuen Antigen detection by immunofluroscencen Nucleic acid detection by PCRIn the sentinel surveillance network JE will be diagnosed by Ig M Capture ELISA, and virus isolation can be done in National Reference laboratoryDiagnosisProbable CasesSuspected case in close geographic and tem

42、poral relationship to a laboratory-confirmed case of JE in an outbreakAcute Encephalitis Syndrome due to other agentA suspected case in which diagnostic testing is performed and an etiological agent other than JE is identifiedAcute Encephalitis Syndrome due to unknown agentA suspected case in which

43、no diagnostic testing is performed / no etiological agent was identified / test results were indeterminateLaboratory WorkuppComplete blood counts: nEarly stage: WBC PMN dominantpPeripheral blood smear - Malarial parasite pBlood glucose pCSF and Blood for serology by IgM ELISA/ virus isolation, CSF i

44、s preferred since by the time patient presents with CNS manifestations the level of viremia in blood has decreased and there is cross reaction with other flavivirusesDifferential DiagnosispNoninfectious conditions:nCNS lupus erythematosusnCNS tumors (nonmetastatic)nCerebrovascular diseasespBacterial

45、 infectionsnPyogenic focal brain abscessnTuberculous meningitisnMycoplasma meningitisnShigellosisnTyphoid fevernTuberculosisnRocky Mountain spotted feverDifferential DiagnosispViral infectionsnArboviral diseases (West Nile virus, Murray Valley encephalitis)nNipah virus infectionnCalifornia encephali

46、tisnEnterovirus infectionnHerpes simplexnDengue feverTreatmentpNo known treatment other than aggressive symptom managementpManagement of JE is essentially symptomaticnRefer the severe to health facilitynAirway and Breathing, ventilation if necessarynConvulsionnCirculationnTemperature control is crit

47、ical, 38PrognosispOnly 1 per 250 Japanese encephalitis virus (JEV) infections results in symptomatic diseasepTwo factors for a good prognosisnhigh concentrations of neutralizing Abs in CSFnhigh levels of JEV IgG in the CSFPrognosispPoor prognostic factorsnAge younger than 10 years nLow Glasgow coma

48、scale nHyponatremianShock nPresence of immune complexes in CSFnPresence of increased amounts of antineurofilament antibodiesnIncreased levels of tumor necrosis factornCoexisting neurocysticercosis nRespiratory dysfunctionnBabinskys signnFrequent or prolonged seizuresnProlonged fevernAlbuminurianHigh

49、 viral replication in the brainNeuropsychiatric SequelaepOccur in 45-70% of survivors, particularly severe in childrenpParkinsonismpSeizurespParalysispMental retardationpPsychiatric disordersLucknow, Northern India. Washington PostVaccines for JE viruspTwo vaccines are manufactured and distributed i

50、n ChinanInactivated vaccine grown in primary hamster kidney cellsnLive attenuated vaccine (SA14-14-2) grown in hamster kidney cellspThe third is manufactured in Japan and distributed abroad by arrangement with Sanofi-PasteurnLicensed as JE-VAXR and is the only FDA approved vaccine for use in the U.S

51、.nHas been in wide use worldwide since the 1960 snThree subcutaneous injections over a month with a booster at 3 yearsn91% efficacy in a large field trial in ThailandSafety of Current JE VaccinepSide effects “ “Generally inconsequential.” ” Local tenderness or mild systemic symptoms in 10-30% - Field s virologypNo neurologic events in Japanese surveillancepInfrequent allergic reactions in adult travelersnUrti