Rabies virus infection An update
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JournalofNeuroVirology,9:253–258,2003c2003Taylor&FrancisISSN1355-0284/03$12.00+.00DOI:
10.1080/13550280390193975
Rabiesvirusinfection:Anupdate
AlanCJackson
DepartmentsofMedicineandMicrobiologyandImmunology,Queen’sUniversity,Kingston,Ontario,Canada
Therearestillmanyunansweredquestionsinthepathogenesisofrabies,butrecentprogresshasbeenmade.Duringmostofthelongincubationperiodofrabies,theviruslikelyremainsclosethesiteofviralentry.Centripetalspreadtothecentralnervoussystemandspreadwithinthecentralnervoussystemoccurbyfastaxonaltransport.Neuronaldysfunction,ratherthanneuronaldeath,isresponsiblefortheclinicalfeaturesandfataloutcomeinnaturalrabies.Recentworkhaschangedourperspectiveontheecologyofrabiesvirusunderparticularcircumstancesincertainspecies.Hopefully,advancesinourunderstandingofrabiespathogenesiswillleadtoadvancesinthetreatmentofthisdreadeddisease.JournalofNeuroVirology(2003)9,253–258.
Keywords:apoptosis;axonaltransport;CNSinfection;encephalitis;geneexpression;neuralapoptosis;neuronalapoptosis;neuronaldysfunction;neu-ronotropism;neuropathogenesis;neurotransmitters;neurotropism;neuroviru-lence;pathogenesis;rabies;rabiesvirus;rhabdovirus;viralpathogenesis;viralreceptor;virulence;virus
Introduction
Rabiesisnormallyarapidlyfatalneurologicaldis-
easeandtodatetherapeuticeffortsinhumanshave
provedfutileexceptinrarecasesinwhichrabiesvac-
cinewasadministeredpriortotheonsetofclinical
disease(Jackson,2002a;Jacksonetal,2003).Abetter
understandingofrabiespathogenesismaybehelpful
inmakingfutureadvancesintherapy.Inthisreview,
selectedtopicsinthepathogenesisofrabies,includ-
ingtheeventsatthesiteofviralentry,transportof
rabiesvirustothecentralnervoussystem(CNS),neu-
ronaldysfunctionanddeath,andnonfataloutcomeof
infectionwillbediscussed.Acomprehensivereview
onrabiespathogenesishasrecentlybeenpublished
(Jackson,2002b).
Eventsatthesiteofviralentry
Thereisalongandvariableincubationperiodinhu-
manandanimalrabies,usuallylasting20to90days,
butsometimesitlastslongerthan1year(Smithetal,
AddresscorrespondencetoDr.AlanC.Jackson,KingstonGen-eralHospital,Connell725,76StuartStreet,Kingston,Ontario,CanadaK7L2V7.E-mail:jacksona@post.queensu.caReceived19August2002;revised8October2002;accepted9October2002.1991).Althoughthereisuncertaintyaboutthepre-
ciseeventsduringthisincubationperiod,adelay
inthemovementofrabiesviruslikelyoccursatthe
siteofviralentryorinoculation.Thebestexperimen-
talanimalstudiestodate,examiningtheeventsthat
takeplaceduringtheincubationperiod,wereper-
formedinstripedskunksusingaCanadianisolate
ofstreetrabiesvirusobtainedfromskunksalivary
glands(Charltonetal,1997).Studiesperformedus-
ingreversetranscriptase–polymerasechainreaction
(RT-PCR)amplificationshowedthatviralgenomic
RNAwasfrequentlypresentintheinoculatedmus-
cle(foundinfourofnineskunks),butnotinei-
therspinalgangliaorthespinalcord,whenskunks
weresacrificed62to64dayspostinoculation.Im-
munohistochemicalstudiesperformedpriortothe
developmentofclinicaldiseaseshowedevidenceof
infectionofextrafusalmusclefibersandoccasional
fibrocytesatthesiteofinoculation.Althoughitis
unclear,theinfectionofmusclefibersmaybeacrit-
icalpathogeneticstepforthevirustogainaccessto
theperipheralnervoussystem.Rabiesvirusbindsto
nicotinicacetylcholinereceptorsattheneuromuscu-
larjunction(Lentzetal,1982),andrecentstudies
usingnerve-musclecoculturesindicatethattheneu-
romuscularjunctionisthemajorsiteofentryinto
neurons(Lewisetal,2000).Twoadditionalputative
rabiesvirusreceptorshaverecentlybeenreported:
theneuralcelladhesionmolecule(Thoulouzeetal,Rabiesvirusinfection254ACJackson
1998)andthep75neurotrophicreceptor(Tuffereau
etal,1998).Theneuralcelladhesionmoleculeisex-
pressedinthreemajorisoformsandexpressionoc-
cursinadultmuscleandattheneuromuscularjunc-
tion(Moscosoetal,1998;Polo-Paradaetal,2001).
Studiesinrodentmodelswithfixedrabiesvirus
strainsindicatethatrabiesvirusiscapableofdirect
entryintoperipheralnerveswithoutareplicativecy-
cleinextraneuralcells,whichisassociatedwitha
shortincubationperiod(Shankaretal,1991;Jackson,
2002b).Thismechanismofviralentrymayrarelyoc-
curundernaturalconditions,suchasaftermultiple
bitestotheheadandneck,associatedwithveryshort
incubationperiods.Studiesinthehighlysusceptible
sucklinghamstermodelalsoshowedearlyinfection
inneuromuscularandneurotendinalspindles(Mur-
phyetal,1973),butinvolvementofthesestructures
hasnotbeendemonstratedinmorenaturalmodels
withlongincubationperiods.
Thevastmajorityofhumanrabiescasesthatoccur
withoutahistoryofanexposurearethoughttobe
duetounrecognizedorforgottenbites,andmolecu-
larcharacterizationoftherabiesvirusvariantshas
indicatedthatintheUnitedStatestheyaremostfre-
quentlyfrombats,particularlysilver-hairedbatsand
easternpipistrellebats(Noahetal,1998).Experimen-