Rabies virus infection An update

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JournalofNeuroVirology,9:253–258,2003c󰀁2003Taylor&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-