Букринская А.Г., Жданов В.М. Молекулярные основы патогенности вирусов
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Ta 6 JI n ll a 12. CTenem, fOMOJJOrHH UMIU!OKHCJIOTHblX noc. C,ll,OBaTCJll,HOCTei:i F-6C,1KOB napaMHKCOBHpycou
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rpmma 1 reJ10BeKa THna 1 noKa3aHa n Ta6JI. 12. Ha1160J1bma.H
roMoJIOr1rn Bbl5IBJICHa y n11pyc0B Ce11J1,ai1 11 11aparpHnna qe,,10BeKa THna 3, HaHMCHblllaH - y PCB [Merson J., 1988]. O6-
napy*eHo cTpyKTypHoc cxoJI.crno Me*JI.Y N-Kom1,aM11 F-6CJIKOB napaMHKC0BHpycon H HA2 Bnpyca rpmma. Om1 coJI.ep.arnT 3Ha1IIITCJibHb!C ytiaCTKH a-cmipaJJH, C0CT05Il!I,HC H3 0CTaTK0B flIJI.pOlf)06IlblX aMHII0KHCJl0T.
I1oKa3aHa HC06XOJI.IIMOCTb fl0CTTpaHcJrnunoHH0f0 npo11,ec CIIHra 6CJ!J{QB CJIH5IHII5l, 33K.!1!01Ia1on1,eroc51 B npoTC0JlHTH'!eCK0M Hape3amm 6eJ1Ka-npemuccrnenm1Ka c 06pa3onaHIICM H0Boro N-KOHU3, KOTOpb!H o6JI3JJ,3CT CJIHB3IO!II,CH aKTHBHOCTb!0. y BH pycon rpmma CJ111BaIOllI,eH 3KTHBH0CTh!0 o6J13/LaeT K0Heu Ma JIOl1 reMarrJIIOTHHHpy10u1,eii cy61:,e;urnHUbI (HA2) rrncJJe Hape3a1rnH HC3KTHBHoro rrpeJI.mecTBCHHIIKa HAO. F-6e.nKn napa MIIKC0BHpycon CHHTe3HPYIOTC5I K3K IIC3KTHBllbIC npe,rnuecT BCIHIHKII H npno6peTaIOT lpy11Kunouam,ny10 aKTIIBH0CTb nocJJC napC33HH5I KJlCTO'!HOfi Tp!!llCIIHOITOJI.06HoA npOTC330A Ha JI.BC cy61:,e;urnnu1>1 Fl II F2, cnH3aHm)re JI.HeyJihcjiH;1.L11Mr cB.ll3bIO. Hape3am1e Bhl3hIB3eT KomjJOpMauuo1rnoe H3MeHeIIHC M0JleKy
.llhl H 3KCI101Hip0B3HHC BH0Bb o6pasonamroro N-KOHU.3, I'JI.C ua X0JI.HTCH CJIIII3aJOllI,Hfi flCIJTHJi. Hape33HHC ocyu1,CCTBJ15II0TTpH0· CHHOITOJJ,06Hhle ¢cpMeHThl KneTKH.
B11pyc1rnJJ,yu11pona1rnoe cmornne K.TTeTotrn1,1x MeM6pan CBH· 33110 C ,'I,eCTa6IIJ1H33UIICH II peopHeHT3UHCJ1 JIIIIIH)J,0B 6HCJ105l, o6ycJIOBJICHllblMH BHpycHblM 6eJIKOM CJlIHIHIUI. B M0;'LCJlbHb!X CHCTeMax areHn,r, K0T0]Jh!C )J,CC'ra6HJIII3Hpy10T JlHIIHJI.Hbd! 6H CJ10H, TaK)l{C Bbl3b!BaI0T C.Jll:UTH!le. Hanponrn, CHHTCTH'lCCKHe neIITHJI.LI, K0T0pblC CT361IJlll3HJ)YIOT JlllllH;'LHhlif 6HOCJ10H, 6JIO KIIpyIOT cJrnmme [Epand R. et al., 1987]. Cmrnmre 3¢¢eKTIIB110 1rnrn611pycT CIIIITCT!11ICCKJIM 0JIIff0flCITTH)J,, KOTOpblfI roM0-
.rI()!'ll 'l('ll N-KOIIHY Mo.ncKy.rn,r 6e.nKa c.. 11rHJIIIH 1rnpyca Cc11;1.ai1.
ilenn1.n, noJ].aB.nReT penmrnau.1110 BrrpycoB rpmma rr p.H,11,a na
paMuKconapycon nyTeM |
6JIOK11poBK11 |
npo11111rn0Be1m.H nupyca |
B KJieTKY [Choppin P., |
Compans R., |
1983]. l1ttrn611pyJOw.ee |
Ae:ikTBHC Ha CJIH51I!He MeM6pan OKa3bIBaeT l'H,ll.po¢o6HL,IH J.1,HK Jlll'leCKHl1 OJIHronerrTHA 11.HKJ1oc11opHH A, 06.r1a,n_a1ow.H11 HMMY· HocynpeccopHo!f aKTimHOCTbIO [Epan<l R. d al., 1987]. Urnrno cnopHH 06Hapy}KirnaeTc51 B nJia3MaTH'lCCKI1X MeM6pa1rnx 06pa60TaH1lbIX KJICTOK H, IIO·BH,ll,HMOMY, 06ycJIOBJ11rnaeT cTa6H.mr3au.1110 JlHJlll)].HOro 6HC.105L
6Jiaro,11.ap51 H3JUl'lHIO 6eJIKa CJ!l!SIHl!51 BBpycLI MoryT l:lbl3B3Tb CJIH.HHHe COCC,ll,HUX KJJCTOK C o6pa30B8HHCM rHr8HTCKHX
MHOr05IJLCj)Il!,!X KJICTOK - CHMJlJiaCTOB H CHHUJITHCl3. HaH60· JJee 81(Till3HOC CHMIIJJaCTOo6pa3oaaHne BLI3bll33IOT ):l.Be rpynnbI
B11pyc0B - napaMHKCOBHj))'CbI H Bl1l.J.
l1apaMHKCODHpycLr Bbl3h1B3JOT c.rrmrnue coce):l.HHX KJICTOK nyTeM ,neHCTBH5! .rr.nyx pa3Ml11Hb!X MCXaHll3MOD: CJIJUIHHe H3BHe H CJl!UlHIIC H3HyTpH. CJ1HHHHe H3BHC npOHCXO,ll,11T npn BblCOKOH MHO)l(CCTBCHHOCTH 3apa:iKCH1151, HOHBJIHCTC5I 1101lTII cpa3y )Ke
noc.rrc 3apa,t{eH1rn II HC Tpc6yeT CHl-!TC3aKOJUip)'CMbIX BupycoM 6eJJKOB. C;rnm111e l!3HYTPII 061rnpy)KfmacTC5I IIpu m1:1Ko11 MU0-
;,1<ecrncuuocTH 3apameHII5f, IIOHBJO]Cl'CH na 1103)1.HHX CTa;nrnx m1(j:Je1rn,1-111 H o6ycJIOBJlel!o lJIIODl., CIIHTC311poBaIIHbL\1. 6e.'!l(OM
CJ!lHIHIUI. CJlllH!IHC H3BHC xapaKTepuo )].JIH napaMHKCOBttpycoB 11 Bl14, B TO apeMJI KaK c.,mHHHC H3IJYTPH onncauo 11 )].JlH rm pycoB )J.pyrux ceMe1krn - repnecnapycon, pcTpoBnpycoB, BH·
pycoe rpHrrrra (npu HH3KHX 3Ha4eHnHx pli) 11 ,n_p. EcrecTBeH Ho, '-ITO CHMrJJJaCT006pa3oeaH11e o6yc,10J3J!CHO TCM )KC 6eJrK,JM CJlH5lHIUI, KOTOpblH Y'IaCTBYCT D npollHKHOBeHHH 1:rnpyca ll
KJleTKy.
DCJIOK CJ!l151lllf51 napaMHKCOBllpycon OTJ!HtiaeTC51 cnoco6-
IIOCTblO Bbl3bJBaTl, CJlll}llIHC npH Hett:rpaJ11,HblX 3Ha,remrnx pH [Nagai Y. d al., 1983]. l1MCHHO c .3THM CB5I3aHa yHirnaJlbHa}:I
cnoco6HOCTb Illlpyca CeHJJ,311 npOHHK3Tb B KJieTKY nyTeM CJJ!UI· mm C IlJl83MaTl1'IeCKOI°l MeM6paHOll, MIIHYH OObi'lHbli'i flY'fh .3H
.II.OU.IIT033. O,n1rnKo }i,pyrof1 napaM11Kco11npyc, mipyc naparpnn na 4eJ10BcKa Tima :3, 11cnoJ11,3yeT pyT1111Hblll nyTb peu.enTop1-1oro 3HJJ.01.l.HT03a, XOT5I ero 6CJIOK CJIH51HH51 rjJ)'Hl{ll,llOHHpyeT npu HettTpclJ!bHOM 3Ha4CHH!I pH (pHC. 4) H CJIHHHliC MeM6paH, 803· MO/KHO, ocyw.ecTBJ151€TC}I fl oco6bJX 3H,ll.OCOMax C HettTpaJu., HblM, a He C KHCJlblM 3H34CHIICM pH. GeJJKll CJJll51Hlrn JJ.pyrnx o60J10'Ie'IHbIX 1rnpycon, T3KllX KaK BHpycLI rpmrna THna A, B n C, ne3H1<ym1pHoro cToMaTHTa, 6eweHcrna, JJecon CeMJIHKH, CHH)l.6nc, )!,CJJTOH .111xopa,!1,KH, 6yHhSIDHpycon, aupyca 3n wTei'ma - Eapp [crvr, Bukrinskaya A. G., 1987], Tpe6y10T
/1,.1151 npoSIBJlCHH51 aKTHBHOCTH HH3KHX 3HalJeHHi"! pH |
(5,0-5,5). |
5• |
67 |
1.0 |
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Puc. 4. 3a[rnCHMOCTb OT pH cmrn:mrn M<':M6pa11 y pa.3Jl!l'lllhlX BHpycoa [ByKpmtcKafl A. r. II AP-, 1987].
Oqm1 errnhle |
n11pych1: I - rplllma; 2 - CeuAall; 3 - rraparpmma qenooeKa |
rnrra 3. |
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y Bnpyca rp1rnna 6eJJKOM CJIH5lHHH HBJrneTCH TOT )Ke 6e.'10l<, KOTOpblH o6ycJIOBJJI1BaeT npHKpeITJleHI-Ie BHpycH0!i lJaCTHl{hl J( KJJeTOlfHOH noaepXH0CTH,- reMarrJJJOTIJHHH. O,LJJial<O cpyHKI{HH rrpHKpemneJ!bH0f0 6eJ1Ka H 6eJll<a CJJll5lHHH «pa3,neJJeHbl» MC}K ,ny pa3HblMH y<JaCTKaMH reMarrJOTHHHHa. I'e11rnrrJl!OTHHHH CIUI Te3HpyeTCH KaK II0Jllme1n11,n-rrpe,nmeCTBCHHHK, KOTOpbIH nape3aCTCH KJICT0lfHblMH TpHrrc1rnorro,no6Hf,IMli nporea3aMH Ha ,11.ne
HepaBIIble cy6be,ll.HHHUhl - 60Jibtuyro H M3JJyJO. YY8CTOK 60Jib WOli cy6be,ll.HHHUbI (HAI) s o6JJaCTH peuemopHoro KapMaHa
BblII0JIHHer ¢y1mumo Y3HaaaHHH pel{eCTTOpa, BH0Bb o6pa30B8H
Hb!H rrpn Hape3aHHH rrpe.n.wecTae1mHKa N-I<OHel{ M3JlOH cy6r, e,nHHHUbI HA2 - q>yHKUH!O cmrnmrn.
Hsyire1me CBOlfCTB 6eJ1K0B CJJ!rnmrn II03BOJIIJ.ll0 o6bHCHlfTb poJ!b HH3KHX 3Hat1eHHli pH ,ll.JlH np05IBJJemrn HX 8KTHBH0CTH. A1 HJI.ll·q.JHKau1rn KJ1erocrnbIX saKyo.r1ei-i rrpH .3HJI.0l{HT03e cjJH3HO JI0flllJCCKHX JlHf8H,ll.0B Heo6xo,n_11Ma ,[(JUI ).IJICCOLI,llal{HH K0MTIJleK C0B JrnraH)l_0B C pel{enTOpaMH Ii )1-JlH peIUIKJrnpoB IHIH peu,en T0p0B. PoJib HH3KHX 3Ha4ettait pH .ll.Jm HHJLYUHposa1rnoro BH pycoM CJIH5IHH>! MCM6paH 1rna51: npu T3KHX 3Ha4eHHHX pH Heo6paTHMO H3MeHHeTC5l KOHcpopMaUH51 6eJIKa CJIHHHIUI, B pe3YJJbT3Te '!ero Ha nosepXH0CTH 6eJIK0BOH M0JleKyJ'lbl .3KCil0HH
py10TCH TI0CJle,1.1,0BaTeJibH0CTH I'II,11,pOc.p06HblX aMHH0KHCJ!OT, ocy |
|||
ll..(eCTBllHI0ll.Uie cmrmme |
[Skehel |
Y. et a1., |
I 982; Doms R. |
ct al., 1985; Gething M. |
et al., |
1986]. O6uapy}KeHbl H3MeHe |
|
HHe aHTHfCHl-!blX CBOHCTB reMarrJH0THHHHa rrpH Cl·ll111{CHllH pH
68
ti I10HB.r1emw HOBbIX aHTiffCHHblX ,neTepMIIHaHT [Doms R, He lenius A., 1986]. 3aBIICHMOCTb cmmaion eii aKTIIBHOCTII OT Hll3KHX 3Haqemu1 pH no,nrnep1KJ1_aeTcH cxo,nHOH }1-HHaMHKOII cmrn mu1 II 113MCHCHH5I KOHcjJOpMal.l)IH rel\rnrrJIIOT!IH!rna npll pH 5,6: y MYTaHTOB m1pyca rpmma, KOTOpbie cnoco6Hbl K CJIH5IHlllO MeM6pa11 npH 6oJJee BbfCOKIIX 3Hl:l11emrnx pH, KOHq)OpMaIJ,HOH
Hl,IC ll3MCHCHH51 6eJJKl:l CJU151HH£ npOHCXOAHT npH COOTBCTCTBCH HO ooJiee BbICOKnx 3Ha'-!emrnx pH [Doms R. et al., 1986; Get hing M. et al., 1986].
Ta 6 JI H l\ a 13. |
311a'ICHHC pH npH CJIHffllHH |
MCMOpa11 |
|||
H reMOJIH3e, HIIA)'l\Hponam10M MyTaHTaMH |
BHpyca |
rpHnna |
X 31 |
||
|
(H3N2) |
|
|
-- |
--- |
|
|
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|
||
|
pH 11pn cmrnHmi |
|
|
||
J'IOKlUIH:1m.1,ast MYTCl[lHH |
MeM6pau |
l pH npu reMomue |
|||
HA2 6
HA2 112
HA2 54
HA2 114
HA2 |
81 |
HA2 |
9 |
HA2 Il2 |
|
HA2 |
47 |
HA2 105
HA2 112
HAI 17
HAI 17 CranAapTllblii BHpyc
0,5 0,5
0,3 0,5 o,4 0,4
0,8
0,5 0,3 0,4
0,9
0,8
5,6
0,3 0,5
0,3
0 6
0:3 0,5 0,6
0,4
0,3 0,3 0,9
0,8
5,5
9:aCTO ; ml OIJ,CHKII cmmaromeii aKTliBHOCTH BHpyca HCJ10Jlb3YIOT TaKoi'1 npocToii TCCT, KaK reMo.rrns. Xon1 npo1 eccb1 reMo Jlll3a II CJJIUIHHH HCOAH03Hal!HbI, TCM He MCHee TaKoe corro CTaBJJCHHe orrpaB,ll_allO. HarrpHMep, 6bIJIO npOBCACHO cpaBHCHIIC crroco6ttocrn pH,na MyTaHTOB BHpyca rp1rnna nrna A (H3N2) reMOJlli3HpoBaTb 9pi!TpOWITbl '-!Ce10BCKa 11 cmrnaron eii aKTHB HOCTH, orrpe,neJrneMoii no nepeHocy 3nepnrn peso1rnnca npn IICIIOJlb30Bl:lHIIH JIHTIOCOM C cpmoopecueHTHb!Mll 30HAaMII. I(aK
BHAHO !13 TaOJI. 13, H3MCHCIIH5! pH ,LI.J.rn cmrnaromei'I aKTHBHO CTI! II reMOJJH33 6blJI!l CXO,ll_Hbl [Wharton S. et al., 1986]. I1c
TIOJib30BaHHblC MYT3HTbl OTJlll'IaJIHCb I10BblillCI!HOH ycTOH'Ill BOCTblO K JJ_CHCTBHIOpeMaHT3AHHa. TIO-BHAHMOMY, cnoco6nocTb Bbl3b!Bl:\Tb CJlll5lHHC MCMopaH TipH OOJiee BbICOKOM 3Ha'-!CHH!l pH l103BOJ1HeT npeOJJ_OJICTb 3HTIIBHpycHblH 3cj1cpeKT npenapaTa, CBH33HHbIH c ero cJtaooocHoBHbIMH CBoikrBaMH. Mb! cpaBHH BaJIH OI1THMaJibHblC 3Ha4CHil5l pH AJIH reMOJJH3a, Bbl3BaHHOro
69
-..J |
Ta 6 JI u ll a 14. 3aBHCHMOCTb |
OT |
pH reMOJIHTlfl{eCKOH 1t He.ipaMHllH,!J,a3HOH |
aKTHBHOCJ'lf sapuaHTOB rpttnna, |
0 |
'IYBCTBHTe. bHblX |
H |
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npH 540 HM) |
|
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llpH pH |
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fHpyc |
I |
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I 5,0 |
I 3,5 |
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KYTI |
|
(HJNl) |
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y |
0 |
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|
0,41 |
0,87 |
|
0,15 |
|
0,11 |
|
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y |
0 |
|
|
0,44 |
0,81 |
|
0,04 |
|
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||
CCCP/090/77 |
(HIN 1) |
|
y |
0 |
|
|
0,52 |
0,39 |
|
0,03 |
|
0,03 |
|
||||
|
|
|
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|
y |
0 |
|
|
0,12 |
0,11 |
|
0,02 |
|
0,01 |
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AHll |
Apoop/57 |
(H2N2) |
|
4 |
0 |
|
|
0,51 |
0,76 |
|
0,07 |
|
0,07 |
|
|||
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|
|
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|
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0 |
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0,50 |
0,62 |
|
0,03 |
|
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1/77 |
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4 |
0 |
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0,34 |
0,38 |
|
0,02 |
|
0,02 |
|
|||
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0 |
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|
0,40 |
0,66 |
|
0,02 |
|
0,01 |
|
||
Hetip3.\H!HHJJ.a3H35I aKTHBHOC.Tb npu pH
|
I |
|
|
I |
|
I |
j |
|
|
|
|
||||
.+,5 |
|
5,0 |
5,5 |
|
6, 0 |
|
G |
0,25 |
|
0,33 |
0,55 |
|
0,40 |
|
0,40 |
0,20 |
|
0,30 |
0,35 |
|
0,47 |
|
0,35 |
0 |
|
0,15 |
0,30 |
|
0,37 |
|
0.22 |
0 |
|
0 |
0,25 |
|
0,28 |
|
0,33 |
|
|
|
|
||||
0 |
|
0,32 |
0,38 |
|
0,35 |
|
0,32 |
0 |
|
0,22 |
0,38 |
|
0,40 |
|
0,35 |
0 |
|
0,17 |
0,32 |
|
0,30 |
|
0,22 |
0 |
|
0,1.5 |
0,17 |
|
0,25 |
|
0,30 |