LYSSAVIRUSESLYSSAVIRUSESJoe McCormackJoe McCormackUniversity of QueenslandUniversity of QueenslandMater HospitalsMater HospitalsSouth BrisbaneSouth Brisbane

Causes of acute encephalitisCauses of acute encephalitis

Herpes simplex virus type 1 (type 2 in neonates)Herpes simplex virus type 1 (type 2 in neonates)ArbovirusesArboviruses: Murray Valley and Kunjin (Australia); : Murray Valley and Kunjin (Australia); Japanese B encephalitis (SE Asia, Papua New Japanese B encephalitis (SE Asia, Papua New Guinea, far N Queensland); West Nile (Africa, W Asia, Guinea, far N Queensland); West Nile (Africa, W Asia, Middle East, N America).Middle East, N America).CMVCMVEBVEBVHIVHIVOther: Lyssavirus, Hendra/Other: Lyssavirus, Hendra/NipahNipah, enteroviruses, , enteroviruses,

adenoviruses, polyoma, influenza, Mycoplasmaadenoviruses, polyoma, influenza, MycoplasmaYung et al Yung et al Infectious Diseases: a clinical approachInfectious Diseases: a clinical approach IPC, Melbourne, 2IPC, Melbourne, 2ndnd edit 2005 edit 2005

OutlineOutlineA short quizA short quizVirologyVirologyPathogenesisPathogenesisEpidemiology: humans and animalsEpidemiology: humans and animalsDiagnosisDiagnosisClinical featuresClinical featuresManagementManagementQuiz answersQuiz answersConclusionsConclusionsAcknowledgementsAcknowledgements

The number of The number of annual human annual human deaths from deaths from rabies in the rabies in the world is:world is:25,00025,00035,00035,00045,00045,00055,00055,00065,00065,000

Rabies: true/falseRabies: true/false

Transmitted as a lab accident in 1 personTransmitted as a lab accident in 1 personTransmitted from cornea of an organ Transmitted from cornea of an organ donordonorThere have been only 4 survivors There have been only 4 survivors Axonal transmission occurs at 20 mm/dayAxonal transmission occurs at 20 mm/dayPhylogenetic classification is based on G Phylogenetic classification is based on G protein protein

European bat lyssavirus: true/falseEuropean bat lyssavirus: true/false

Has been found in a Has been found in a human in northern human in northern EnglandEnglandOnly 5 human cases Only 5 human cases have been describedhave been described

Where outside Australia has ABL Where outside Australia has ABL been found? been found?

New ZealandNew ZealandNew CaledoniaNew CaledoniaPapua New GuineaPapua New GuineaMalaysiaMalaysiaVietnamVietnamPhilippinesPhilippines

Lyssavirus classificationsLyssavirus classifications

7 genotypes + 7 genotypes + ““other Eurasiansother Eurasians””2 phylogroups: 2 phylogroups:

1 1 –– Rabies, Duvenhage, EBLV, ABLVRabies, Duvenhage, EBLV, ABLV2 2 –– Lagos bat, MokolaLagos bat, Mokola

Lyssavirus classificationsLyssavirus classifications

7 genotypes + 7 genotypes + ““other Eurasiansother Eurasians””2 phylogroups: 2 phylogroups:

1 1 –– Rabies, Duvenhage, EBLV, ABLVRabies, Duvenhage, EBLV, ABLV2 2 –– Lagos bat, MokolaLagos bat, Mokola

Single stranded RNA, neurotropicSingle stranded RNA, neurotropicRhabdoviridiaeRhabdoviridiae familyfamilyMononegaviralesMononegavirales order (others: order (others: FiloFilo--, , BornaBorna--

ParamyxoParamyxo--))

Lyssavirus genotypes: geographyLyssavirus genotypes: geography

KyrghystanKyrghystan, Tajikistan, , Tajikistan, RussiaRussia

Aravan, Khujand, Aravan, Khujand, Irkut, West Irkut, West caucasiancaucasianbatbat

otherother

Australia; Philippines ?Australia; Philippines ?ABLV a/bABLV a/b77

UK, Holland, Germany, Ukraine, SwitzerlandUK, Holland, Germany, Ukraine, SwitzerlandEBLV type 2 a/bEBLV type 2 a/b66

Holland, Denmark, Germany, France, Spain, Holland, Denmark, Germany, France, Spain, Poland, Hungary, Russia, UKPoland, Hungary, Russia, UKEBLV type 1 a/bEBLV type 1 a/b55

Southern AfricaSouthern AfricaDuvenhageDuvenhage44

AfricaAfricaMokolaMokola33

AfricaAfricaLagos batLagos bat22

All continents except All continents except Australasia, AntarcticaAustralasia, Antarctica

RabiesRabies11

Rabies: global distributionRabies: global distribution

Rabies: Rabies:

ABLV: Alex Hyatt, AAHL GeelongABLV: Alex Hyatt, AAHL Geelong

The virusesThe viruses……

Bullet or rod shaped, 80 x 180 nmBullet or rod shaped, 80 x 180 nmRNA genome 11,615 RNA genome 11,615 –– 11,966 kb11,966 kbNucleoprotein (N) Nucleoprotein (N) –– most conservedmost conservedPhosphoprotein (P) Phosphoprotein (P) –– most variablemost variableMatrix (M)Matrix (M)Glycoprotein (G)Glycoprotein (G)RNA polymerase (L)RNA polymerase (L)

Lyssaviruses: phylogeny based on N proteinLyssaviruses: phylogeny based on N protein

Viral proteinsViral proteins

N, P, L form ribonucleoprotein with RNAN, P, L form ribonucleoprotein with RNAM, G involved with budding & assemblyM, G involved with budding & assemblyN most commonly used for diagnostic assays, N most commonly used for diagnostic assays, sequencing, epidemiologic markingsequencing, epidemiologic markingP transcription, replicationP transcription, replicationM assembly, transcription, host cell suppressionM assembly, transcription, host cell suppressionG forms surface spikes: host cell binding & G forms surface spikes: host cell binding & entry, axonal transport, neutralizing Abentry, axonal transport, neutralizing AbL transcription, replicationL transcription, replication

Lyssavirus pathogenesis (1)Lyssavirus pathogenesis (1)

Local replication in nerves & musclesLocal replication in nerves & musclesAxonal transport 50Axonal transport 50--100 mm/day100 mm/daySpread to salivary glands, tongue, larynx, Spread to salivary glands, tongue, larynx, heart, cornea, GI tract, adrenal glandsheart, cornea, GI tract, adrenal glands

Charlton Charlton ActaActa NeuropatholNeuropathol BerlBerl 1997 1997 9494: 73: 73--77TsiangTsiang AdvAdv VirusVirus ResRes 1993 1993 4242: 375: 375--412412Jackson Jackson LabLab InvestInvest 1999 1999 7979: 945: 945--5151

Lyssavirus pathogenesis (2)Lyssavirus pathogenesis (2)

Neuroinvasiveness: EBLV 2 > RABV > Neuroinvasiveness: EBLV 2 > RABV > EBLV1 > ABLV (EBLV1 > ABLV (mousepad inoculationmousepad inoculation))Disease following intracerebral or intraDisease following intracerebral or intra--muscular injection [ic only phylogroup 2]muscular injection [ic only phylogroup 2]Bats, miceBats, mice

Brooks Brooks VaccineVaccine 2005 2005 2323: 4101: 4101--99BadraneBadrane JJ VirolVirol 2001 2001 7575: 3268: 3268--7676Almeida Almeida EpidemiolEpidemiol InfectInfect 2005 2005 133133: 523: 523--77

Lyssavirus pathogenesis (3)Lyssavirus pathogenesis (3)G protein: G protein: binds via nicotinic acetylcholine binds via nicotinic acetylcholine receptor, neural cell adhesion molecule & p75 receptor, neural cell adhesion molecule & p75 neurotropinneurotropin receptor (EBLV2 & RABV)receptor (EBLV2 & RABV)Virulence abolished by mutation at Virulence abolished by mutation at argarg 333 in 333 in antigenic III site of G proteinantigenic III site of G proteinEnhanced entry/fusion & virulence by change of Enhanced entry/fusion & virulence by change of AA 194 AA 194 asnasn to to lyslysOther virulence determinants studied on G, M, P Other virulence determinants studied on G, M, P and N proteinsand N proteins

Lentz Lentz ScienceScience 1982 1982 215215: 182: 182--4; 4; ThoulouzeThoulouze JJ VirolVirol 1998 1998 7272: 7181: 7181--90; 90; DietzscholdDietzschold ProcProc NatlNatl AcadAcad SciSci USAUSA 1983 1983 8080: 70: 70--4; 4; SeifSeif JJ VirolVirol 1985 1985 5353: : 926926--34; 34; TuffereauTuffereau VirologyVirology 1989 1989 172172; 206; 206--12; Faber 12; Faber JJ VirolVirol 2005 2005 7979: : 1414114141--8; Shimizu 8; Shimizu VirusVirus ResRes 2007 2007 123123: 154: 154--6060

Lyssavirus pathogenesis (4)Lyssavirus pathogenesis (4)

Changes in length of intergenic regions Changes in length of intergenic regions affect proteins produced, cell adaptation affect proteins produced, cell adaptation and neuroinvasivenessand neuroinvasivenessNeurons that avoid apoptosis have lower Neurons that avoid apoptosis have lower viral replication and slower invasivenessviral replication and slower invasiveness

Marston Marston J Gen J Gen VirolVirol 2007 2007 8888: 1302: 1302--1414WarrilowWarrilow VirologyVirology 2002 2002 297297: 109: 109--1919Faber Faber Proc Natl Acad Sci USAProc Natl Acad Sci USA 2004 2004 101101: 16328: 16328--3232

The major reservoirsThe major reservoirs

The major transmitterThe major transmitter

Lyssavirus genotypes: reservoirsLyssavirus genotypes: reservoirs

Insectivorous batsInsectivorous batsAravan, Khujand, Aravan, Khujand, Irkut, West Irkut, West caucasiancaucasian batbat

otherother

Insectivorous + fruit bats Insectivorous + fruit bats ABLVABLV77

Insectivorous batsInsectivorous batsEBLV type 2EBLV type 266

Insectivorous batsInsectivorous batsEBLV type 1EBLV type 155

Insectivorous batsInsectivorous batsDuvenhageDuvenhage44

Shrews, catsShrews, catsMokolaMokola33

Fruit batsFruit batsLagos batLagos bat22

Wide range of mammals; bats Wide range of mammals; bats in Americasin Americas

RabiesRabies11

Human rabiesHuman rabies55,000 deaths/y55,000 deaths/y

Mostly Asia & AfricaMostly Asia & AfricaIndia highest incidence >> 10,000 cases/yIndia highest incidence >> 10,000 cases/yChildren < 15 represent 30Children < 15 represent 30--50% of cases50% of casesMany cases & deaths unreportedMany cases & deaths unreportedAll continents except Antarctica/AustralasiaAll continents except Antarctica/AustralasiaMainland > islandsMainland > islands

www.who.int/rabies/en/www.who.int/rabies/en/

Animal rabies: DOGSAnimal rabies: DOGSMajor vectors & responsible for most human casesMajor vectors & responsible for most human cases

Significant reservoirs includeSignificant reservoirs includeArctic foxesArctic foxes: northern America/Europe/Asia: northern America/Europe/AsiaCoyotes, skunks, raccoonsCoyotes, skunks, raccoons: Americas: AmericasJackals, raccoon dogsJackals, raccoon dogs: Europe/Asia: Europe/AsiaMongooseMongoose: Africa/Asia/Caribbean: Africa/Asia/CaribbeanWolves, catsWolves, cats infected but not significant reservoirsinfected but not significant reservoirsRodents, lagomorphs, birdsRodents, lagomorphs, birds can be infected experimentallycan be infected experimentallySeveral cases dogs Tasmania 1867Several cases dogs Tasmania 1867

Rupprecht Rupprecht Lancet Infect DisLancet Infect Dis 2002 2002 22: 327: 327--4343