measles virus pathogenesis

8/9/2019 Measles Virus Pathogenesis

1/12


2/12

including the sin, con(unctivae, lung, gastrointestinal tract, liver, idney and genitalmucosa, are also aGected 2all et al., 1B14 Koune et al., 1BB


3/12

icistronic m0)A and the V protein is translated rom V m0)A, /hich is ormed aterinsertion o a single nucleotide E y 0)A editing.

MV /as ?rst isolated in 1B$7 y using primary culture o human idney cells Lnders @eeles, 1B$7-. :his ?rst isolate, the Ldmonston strain, is the progenitor o the currentlyused live vaccines. +use;uently, Vero cells derived rom Arican green money idney

/ere commonly used to isolate viruses rom clinical specimens. 2o/ever, isolation /ithVero cells /as rather inefcient and usually re;uired lind passages. :his situationchanged dramatically /hen Koune et al. 1BB6-sho/ed that the Lpstein>arr virusLV-#transormed marmoset #lymphoid cell line B$#! and its suline B$a are highlysusceptile to viruses rom clinical specimens. mportantly, B$a cell#isolated MV strainsretain pathogenicity to e*perimentally inected moneys, unlie Vero cell#isolated strainsKoune et al., 1BB6, 1BB


4/12


5/12

nitric o*ide y macrophages Sang et al., "667-. More recently, +3AM /as ound to e amarer or haematopoietic stem cells in mice Kiel et al., "66$-.

Receptor usage and tropism of MV

LrlenhRer et al. "66"-e*amined a panel o MV strains, including vaccine and /ild#typestrains /ith various passage histories, and ound that +3AM acts as a common receptoror all MV strains tested. n act, no MV strain has ever een reported that does not use+3AM as a receptor, e*cept or arti?cially generated +3AM#lind recominant viruses seeelo/-. n general, #cell line#isolated strains utilie +3AM, ut not 5D7receptor interaction allo/ing onlyinefcient entry may not lead to apparent cell>cell usion. :he +3AM# and 5D7


6/12

Vie/ larger versionN

n this page n a ne/ /indo/

Do/nload as @o/er@oint +lide

Fig. 3.0eceptor usage o MV in vivo. MV inects cells mainly y using +3AM as a receptor. t mayalso inect cells, aleit inefciently, via Zreceptor [\. t is not no/n /hether MV uses5D7< as a receptor in vivo.

:oll#lie receptor :30- ligands are ound to induce +3AM e*pression on monocytesieac et al., "66"4 Farina et al., "6674 Minaga/a et al., "661-. Furthermore, ieac etal. "66"-sho/ed that the 2 protein o #cell line#isolated MVs acts as a ligand or :30",inducing +3AM e*pression on monocytes. :his ?nding suggests an interesting mechanism

y /hich MV induces its o/n receptor on potential target cells, such as +3AM =ut:30"9monocytes.

Morbillivirus receptors

MV is classi?ed in the genus Morbillivirus, together /ith Canine distempervirus5DV-, Rinderpest virus0@V-, Pestedespetitsruminants virusand several othermorilliviruses o a;uatic mammals Erifn, "661-. All o these viruses are lymphotropicand cause devastating diseases in their respective host species, accompanied y severelymphopenia and immunosuppression. :he common tropism and pathology omorilliviruses prompted :atsuo et al. "661-to e*amine several strains o 5DV and 0@Vor receptor usage. :hey sho/ed that all 5DV and 0@V strains e*amined use canine andovine +3AM, respectively, as receptors.t has een difcult to otain ?eld isolates o 5DV in culture. :hey are usually isolated y

cocultivation o lymphocytes rom dogs suspected to harour 5DV /ith mitogen#stimulated dog lymphocytes Appel et al., 1BB"-. Field isolates o 5DV are also reportedto replicate in dog and erret macrophages Appel %ones, 1B


7/12

isoorms can act as receptors or these MV strains. n the other hand, +3AM serves as areceptor or all MV strains. Although murine +3AM has unctional and structural similarityto human +3AM, it cannot act as a receptor or MV no et al., "661-. :he V domain ohuman +3AM is necessary and sufcient or MV receptor unction no et al., "661-Fig.J"W- and three amino acid residues, at positions


8/12

ind to overlapping, ut distinct, interacting suraces in the Ldmonston 2 protein+antiago et al., "66"-. Vongpunsa/ad et al. "667-successully generated viruses+3AM#lind MVs- that laced the aility to ind +3AM y introducing sustitutions atrelevant positions e.g. D$86A-.von Messling et al. "66$-perormed a similar analysis or the 5DV 2 protein andidenti?ed several residues involved in +3AM#mediated usion support and virus entry.

:hose residues are also grouped in t/o clusters located in propeller##sheet $, and de?neregions analogous to those de?ned or +3AM#relevant residues in the MV 2 protein. Shena 5DV strain /as adapted to marmoset B$a cells, t/o sustitutions /ere oserved atpositions $86 and $7! o the 5DV 2 protein, one residue in each cluster de?ned in theaove study +ei et al., "668-.n order to retarget MV, recominant viruses that possessed hyrid proteins consisting othe epidermal gro/th actor LEF- or the insulin#lie gro/th actor 1 EF1- lined to thee*tracellular caro*yl terminus o the 2 protein a type memrane protein- /eregenerated +chneider et al., "666-. :he recominant viruses /ere rescued successullyrom cD)As and ound to enter +3AM=5D7< =rodent cells e*pressing the human LEF orEF1 receptor, respectively Fig.J7aO-. +ingle#chain antiodies /ere also usedsuccessully to produce the hyrid 2 proteins and /ere displayed on recominant MVs.:hey could enter cells e*pressing the molecules recognied y the single#chain

antiodies 2ammond et al., "661-. :he viruses retained the aility to inect cells viaauthentic receptors, /hich could e aolished y altering +3AM# and 5D7


9/12

lymphoid organs including the thymus, spleen and lymph node, ollo/ed y inection oepithelial cells at a later stage o inection von Messling et al., "668, "667-. t is possilethat MV inects respiratory epithelial cells as primary targets via the inefcient +3AM# and5D7


10/12

MV 0)A synthesis, protein translation or assemly Vincent et al., 1BBB, "66"-. Anotherpossile mechanism is that MV cannot eGectively counteract F) activity in murine cellssee elo/-.:here is a report that uritts lymphoma regressed ater MV inection luming ]iegler, 1B1-. A similar ?nding /as also otained or 2odgins disease :a;i et al.,1B!1-. LV may e responsile or these diseases and LV#transormed #lymphoid cell

lines have een sho/n to e*press high levels o +3AM Aversa et al., 1BB4 :atsuo et al.,"666-. :hereore, it is possile that these tumours e*pressed +3AM and that MV inectedand illed these tumour cells. :hese oservations provide a rationale or MV#asedoncolytic therapy Erote et al., "6614 )aamura et al., "66$-.

Roles of the V and proteins in MV infection

:he V and 5 proteins encoded in the @ gene are generally considered non#structuralproteins, ut a recent study indicated that the 5 protein is present in MV virions Devau* 5attaneo, "667-. :he V and 5 proteins o many paramy*oviruses have een sho/n topossess F)#antagonist activities 5onelmann, "66$4 2orvath, "6674 )agai Kato,"667-. :he V protein o MV also locs signal transduction in response to F)#&C# @alosaari et al., "6684:aeuchi et al., "668a4 &oota et al., "668-. :he 5 protein o MV/as also reported to inhiit F) signalling +haGer et al., "668-. Furthermore, the V

proteins o paramy*oviruses have een sho/n to ind the 0)A helicase mda#$, thereyinhiiting its activation o the F)##promoter Andre(eva et al., "667-. :30# and #B#mediated F)#&C#production in human plasmacytoid D5s is also inhiited y MV,although involvement o the V or 5 protein has not een determined +chlender et al.,"66$-.+tudies have sho/n that the recominant MV deective in the V protein replicatednormally in cultured cells and @M5s Lscofer et al., 1BBB4+chneider et al., 1BB-, ut itreplicated less efciently and did not e*hiit strong pathogenicity in 5D7


11/12

MV inects cells in vivomainly y using +3AM as a receptor. Use o +3AM =cells e.g.primary human idney and Vero cells- may lead to isolation o MV strains that haveadapted to use 5D7< as an alternative receptor &anagi et al., "66"-. All o the vaccinestrains elonging to the Ldmonston lineage have either or oth &7!1 and E$7< in the 2protein @ars et al., "661-, presumaly accounting or their aility to use 5D7< as areceptor. 5onsidering the high mutation rates o 0)A viruses and the ui;uitous

e*pression o 5D7


12/12

evidence that MV indeed uses 5D7< as a receptor in vivo. MV may also inect, aleitinefciently, +3AM=cells via the +3AM# and 5D7receptor interaction.@revious +ection)e*t +ection

Ac!nowledgments

Se than all memers o our laoratory or discussions. ur /or /as supported ygrants rom the Ministry o Lducation, 5ulture, +ports, +cience and :echnology and theMinistry o 2ealth, 3aor and Selare o %apan, rom the %apan +ociety or the @romotiono +cience and rom the Uehara Memorial Foundation.
http://vir.sgmjournals.org/content/87/10/2767.long#fn-group-1http://vir.sgmjournals.org/content/87/10/2767.long#ref-list-1http://vir.sgmjournals.org/content/87/10/2767.long#fn-group-1http://vir.sgmjournals.org/content/87/10/2767.long#ref-list-1

measles virus pathogenesis

Documents