EbolaDraftKarinMoelling
4.11/1.11.2014/[email protected]
KarinMoelling
IntMedMicrobiol,UniversityZürich
MPIMolGenetics,Berlin,HPIHamburg
[email protected]
00491723274306
ThinkingaboutEbolavirusesintimesofavirusepidemic
WhileadevastatingEbolaVirusepidemicisfrighteningusitmaycomeasasurprisetolearn
thatEbolavirusgenesarepresentinmammaliangenomes.
TheDNAinmammaliancellscontainsmanyviralgenomes,bestknownaretheretroviruses,
whichintegrateasanormalstepintheirvirallifecycle.Howeverotherviruses
integrate“illigitimately“,beingRNAviruseswithnoobligatoryDNAintermediate,which
normallyarenonintegrating.OneofthemareEbolaviruses.Ebolavirusgenescanbetraced
backinthemammaliangenometoabout40to50Mio,someeven100Mioyearsago.Theyare
surprisinglyintact,andeventodayexpresssomeproteins.Theyarerelatedtopresentday`s
acutevirusesfromZaire(Baylietal2010;2010;KatzourakisandGifford2010).Ebolavirusesare
RNA‐containingviruses,theyshouldnoteasilyhaveenteredthegenomicDNA.Howevera
ReverseTranscriptasefromretrovirusesalsopresentinmammaliancellsandalsoingermcells
mayhavehelpedtogenerateaDNAcopyforilligitimateintegrationandtherebyenabled
subsequentverticaltransmissionandinheritance.RetrotransposonssuchasLINEelements
expressReversetransciptasesandmayhavesuppliedtheenzymeintrans.Recombination
eventscouldalsobeinvolved.EbolavirusesexpressthenuclearproteinNCinbats,inother
hostsfragmentsofitandViralproteinvp35,opssumalsopartofthepolymerase.Ebolaviruses
similartoMarburgviruses,anothermemberofthisfilovirusfamily,aremainlyexogenous
viruses,transmittedinSudan,CongooandaroundLakeVictoria.EndogenousEbolaviruseswere
detectedinopossum,whallaey,kangeroos,ratsandinbats,guineapigs,shrewsandmorethan
65Mioyearsagoalsopigs.EbolaandMarburgvirusesmayhaveenteredthegenomes
independently.Otherrelativeswentextant.Itcameasasurprise,thatfilovirusesweredetected
inthegenomesofbatsinNorthAmerica,inAsianprimatesinrodentsinSouthAmericaand
Australia,besidesswineinReston,theonlylocationwhereEbolaoutbreakshavebeen
described.WhatdoesintegrationofvirusesintogermlinesandsurvialasfossilsfrommanyMio
agomean?
AlsoBornaviruses,anotherRNA‐containingviruswithasimliargenomestructureasEbola
viruses,areintegratedasDNAinmammaliangenomeandexpressviralproteinsinhumans.In
contrasttoEbolatheyenteredandwereendogenizedintothehumangenome.
Bornavirusesintegratedinhumans,monkeys,mamosets,elephants,lemuresmouserat,birds‐
butnothorses!Sincetheyareabsentinhorsegenomesonespeculationgoes,thathorsescanget
Bornavirus‐dependentneurologicaldiseasessuchasmentaldepressions,whilehumansare
protectedbyexpressingBornavirusgeneproductsagainstthistypeofdisease.Weget
depressionsforotherreasons.IntegratedBornavirusesexpressviralproteinsthereby
protectingtheirhostsandsurvivedinthegenomestilltoday.WhydidEbolavirusesnotget
endogenizedintothehumangenomeforourprotection?Maybeinfectionofhumansoccurred
toorecently,contactstobatshasbecomecloserthanbefore,possiblyonfoodmarkets,or
infectionofgermcellsmaynotbepossible.IncontrasttothestructurallyrelatedBornaviruses,
EbolavirusesdonotreplicateinsidethenucleusasBornavirusesdo,thereforeBornaviruseshad
ahigherchancetoenterthehosts`DNAgenomes–thisisanexplanationgivenbyA.
Katzourakis(personalcomm.).
About10differentvirusesfoundtheirwayintomammaliangenomesasdescribedby
KatzourakisandGifford(2010).BesidesEbolaandBornaevencircovirusesweredetected
harboringararesingle‐strandedcircularDNA.Circovirusesarefrequentinpigs,chickenand
EbolaDraftKarinMoelling
4.11/1.11.2014/[email protected]
pigeon.Theyareratheruniquebycontainingacircularsingle‐strandedDNAinasmallnaked
icosaeder.
Fromthepublishedliteratureonecanconclude,thatalmostallvirustypesandreplication
strategiesmadeitasendogenoussequencesintomammaliangenomes.Thefrequencymaybe
underestimatedbecausesomeseuqneesmaynolongerberecognizedduetomutations.
Integrationoccursmorefrequentlybyvirusesthatestablishpersistantinfectionsandreplicate
inthenuclesus,yetinsomecasesalsooutside.(AllthisisdescribedbyKatzourakisandGifford,
2010,andBornaandEbolaalsobyBelyi,LevineandSkalka,2010).
Retroviruesinmammaliangenomes
Sequencingofthehumangenomeatthebeginningofourcenturyunraveledsurprises.The
humangenomeandalomosteveryeukaryoticgenomeisfullofDNAprovirusesderivedfrom
retroviruses.Mostofthemarefossils,moreorlessdefective,leftoversfromviralinfections
about35or100Mioyearsago.Upto45%ofthehumangenomeconsistsofretroviralrelicswith
differentdegreesofdeletions.
IntegrationasDNAcopiesmusthavebeenadvantageousforavirus,thisislikeasafeharborfor
maintenance,tobeinheritedandtoproduceprogeny.Thereisalsomutualism,becausethe
integratedvirusesalsoprotectthecells.Thisisofbenefitnotonlyfortheindividualcellbutfor
theentirehostforsurvival.Itisabasicprincipleofallvirusestoprovideitshostcellwithan
antiviraldefenseagainstasimilarinvader.Monopolyofavirusinsideacellisadvantageousfor
thevirustoguaranteehigherviralprogenythaninthepresenceofacompetitor.Itisalsoless
dangerousforthehostcell.Inprinciple,avirusinfectionwillleadto"superinfectionexclusion",
orsimplyspoken:entranceforbidden.Thistermwascoinedforthephage‐bacterialworld‐and
holdsupforthewholevirusworldtilltoday.
Endogenousvirusesprotecttheirhost.
Someexamplesmayillustratetheprotectiveeffectofanintegratedorendogenizedvirus‐best
studiedforretroviruses.Virologistsknowthatonecannoteasilysuperinfectacellwiththesame
virus,designatedasviralinterference.Protectioninsidecellswasdevelopedbymonkeysas
defenseagainstasuperinfectingvirus.TheyexpresstheTRIM1alphaproteindirectedagainst
theGagproteinofanincomingvirus.Evencertainhoneybeesdefendthemselvesbyexpressing
astructuralproteinofanendogenizedvirusagainstsuperinfection(theIsraeliacuteparalysis
virus,anRNAvirus.Ref,seeBelyietal.2010).Alsoaphagecanprotectitshostagainst
superinfectionbythesamephage:aretrophageexpressinganreverstranscriptase.Thephage
doesnotevenhaveanamebutitshostisthewell‐knownbacteriaBordetellapertussis,causing
whoopingcaughs.
EndogenizationofaretroviralDNAasaprotectivemeasurecanbewitnessedinanactively
ongoingrealityshowwithKoalasinAustralia:theseanimalswerethreatenedfromgoingextinct
andwerethereforeisolatedonanislandabout100yearsagotorecover‐yettheopposite
happened.Theycontractedaretroviralinfectionbyagibbon‐apeleukemiavirusandmanyof
themdied.Thesurvivorsexhibitedtwokindsofintegratedretroviralsequences,somefromde
novoinfectionsatvariableintegrationsitesand‐toeverybodiessurprise‐alsoatstable
integrationsitesinallcells(Tarlingtonetal,2008).Thismusthavebeencausedbyfixation
throughgermlineinfectionandinheritance.Theprocessofretroviralendogenizationhappened
intheKoalasinlessthan100years.
Virusesandanitviraldefensearerelated.
Retrovirusesareidealforcreatingantiviraldefense,becausetheyarecellulargenesimmediately
afterinfection,reversetranscriptionandintegrationandundergomutationsbyanerror‐prone
RTduringeachroundofreplication.Thiswillleadtogeneticdiversityandallowselectionof
survivors.itisafastwayforacelltodevelopadefensesystemevenamoregeneralone,notonly
againstidenticalinvaders.ThusretrovirusesasDNA‐provirusesgeneratedimmunitynotonly
againsttheircolleagueviruses‐butareprobablythebasisforageneraldefensesystem.Thus,
ourgenomeandthatofmanyotheranimalspecieshaveaccumulatedretrovirusesasantiviral
defensesystem.Retrovirusescreatedimmunesystems.Thusretroviralsequencesinourhuman
EbolaDraftKarinMoelling
4.11/1.11.2014/[email protected]
genomeprotectedusagainstsuperinfections.Withtime,whenarelatedvirusdidnotshowupas
possibleinvader,lossofselectivepressureresultedinaccumulationofmutationsordeletions
andfinallyloss.
Doweneedtoworry?
SimilarlyilligitimateDNAversionsofanyotherviruswhichbecomesintegratedwillprotectthe
cellagainstsuperinfection.Virusesmaythenstillreplicatebutnotcausediseases.Thisisthe
casewithEbolaviruses.Theywereendogenizedinbats,wheretheyreplicatewithoutcausing
diseasesbutmaybetransmittedtohumans.ThegeographyofbatscarryingendogenizedEbola
sequencesisverysurprisingandindicatesthattheviruswasnotconfinedtoareasinAfrica.
Whataboutbatsinotherplacesintheworld?Whatabouttoday?Batsareaspecieswithmore
than1000types.Ebolawasalsofoundendogenizedinswines.Nobodycanpredictwhatthis
maymeanorwhethertherearetodaypotentialdangersassociated.
References:
Endogenous viral elements in animal genomes.
Katzourakis A, Gifford RJ.
PLoS Genet. 2010 Nov 18;6(11):e1001191
GenomeRes.2006Dec;16(12):1548‐56.Epub2006Oct31.
Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in
vertebrate genomes.
Belyi VA, Levine AJ, Skalka AM.
PLoS Pathog. 2010 Jul 29;6(7):e1001030.
Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae
are more than 40 to 50 million years old.
Belyi VA, Levine AJ, Skalka AM.
J Virol. 2010 Dec;84(23):12458-62.
Initial sequencing and analysis of the human genome.
Lander ES et al Nature. 2001 Feb 15;409(6822):860-921
Identification of the regions of Fv1 necessary for murine leukemia virus restriction.
Bishop KN, Bock M, Towers G, Stoye JP.
J Virol. 2001 Jun;75(11):5182-8.
GenomeRes.2006Dec;16(12):1548‐56.Epub2006Oct31.
Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements.
DewannieuxM1,HarperF,RichaudA,LetzelterC,RibetD,PierronG,HeidmannT.
Biology and evolution of the endogenous koala retrovirus.
Tarlinton R, Meers J, Young P.
Cell Mol Life Sci. 2008 Nov;65(21):3413-21.