Enteroviruses

1
?????????????
???
???????????? ?????????? ????????
??,2011.05.25
2
??????????
?????
3
??????????

• ???????????????????,1909?????????,1949?,?????????
  ????,????????????
• ?????1948??????Coxsackie?,?????????????????,?????
  ?????????????????????????????????????????,???????A
  ??B??
• ????1951???????????????????,???????????????,?????
  ?????????
• ???????,?????????????(6971),??,?????111?

4
?????????
???? ???? ???? ????
??? ?species ?
????(PV) ???
?????A?(CAV) 1-22,24 HEV-A CAV2-8,10,12,14,16 EV71,76, 89-91
?????B? (CBV) 1-6 HEV-B CBV1-6 CAV9 ECHO1-7,9,11-21,24-27,29-33 EV69,73-75,77-88,93,97,100-111
????(ECHO) 1-7,9,11-21, 24-27,29-33 HEV-C ????(PV) ??? , CAV1,11,13,15,17-22,24,
????(EV) 68-71 HEV-D EV68,70,94
4
5

• ? CoxA23?ECHO9?????,???ECHO9
• ? CoxA15?CoxA11?????,?????CoxA11
• ? CoxA18?CoxA13?????,?????CoxA13
• ? ECHO8?ECHO1?????,?????ECHO1
• ? ECHO10????????1?(Reo 1)
• ? ECHO22?ECHO23???????????????,????????????1??2?
  
• ? ECHO28?????1A?
• ? ECHO34??CoxA24,?CoxA24???
• ? ???87?????????68?
• ? ????72????????????????
• ? ??????(SVDV)???Cox B5?

6
??????????

• 30nm
• ??????
• ???

Courtesy of Linda M. Stannard, University of Cape
Town, S.A.h
7
??????????
8
?????????
gt ?-????? ????? gt ????? ???? gt ????
9
?
?
10
??????????????
?? ?????NPEV? ?????????,??

11
???????????????

• ?????????????
• ?????
• ?????????????
• ???????
• ????????????(????)
• ??????HLA?????????????
• ???????????????????B? ?
  
• ECHO?EV71????

12
????
???????,??????,??????????????? ???????????,??????
??,??????????????? ???????????????,???????????????
??? ?????????????
13
??????????????
14
?????????????
15
????

• ?????????,????3-35?,??7-14??
• 90????????
• ?5??????
• 12?????????????????
• ??0.1????????????
• ??????????

16
?????????????
17
?????

• ????? ????????????????????,?
• ??????????,?????
  71?(EV71)
• ?????? ????????????, ?????
• 5?????
• ?? ???????????????????.? ?
• ???????????
• ?????? ?A??????(Cox A16)?EV71??,?
• 
  B????????????????????
• ??? ? A????????
• ??????(??????? ,Bornholm disease)
• ???B????????

18
???????????
????
????
? ? ? ?
????
??????
???
???? ????
1
2
3
4
5
6
14
gt28
?
19
???????????
20
????
???????? 1. ??????
2. ?? 3. ?? 4. ??? 5.???
21
????Hand-foot-mouth Disease, HFMD

• HFMD???????
• HFMD??????????
• HFMD??????
• ??HFMD?????????????
• ????HFMD????????
• ????2008?-2009?HFMD ????
• ???????????
• HFMD????
• HFMD?????

22
????????13???????????
????

• ??????
• ??????,????????
• ?????????
• ????????????
• ??????,
• ????????-2?
• ??
• ????

23
?3. 2008 ?3?1??5?9????HFMD???
24
HFMD???????

• 1.??????????????????
• 2.?????????,??????
• 3.????????,?????????????
• 4.??????????????,???
• 5.?38??????

25
???????????????
4?18,??CDC?????
???????????????HEV71
????
????
?????
??4?23?
EV71???????????
26
?3? 23?4?29??????? (?22?)
?? EV71????
?????? 15
27
15??????????
???? ??? ??()
?? 15 100
???? 14 93.3
???? 12 80.0
?????? 9 60.0
?? 7 46.7
?? 8 53.3
??? 3 20.0
????? 6 40.0
????? 2 13.3
???? 2 13.3
27
28
?????????????EV71?????
?? ?? ??? HFMD??EV71???? HFMD??EV71???? HFMD??EV71????
?? ?? ??? ??? ??? ???
?? 158 147 11 93.04
?? 16 13 3 81.25
29
??2008?3?1?5?9???????HFMD??

• 90?????5?????
• EV71???2008?HFMD??????????

30
?. HFMD??????????
31
HFMD???
HFMD????????????????????,??????????????? ????????
?,??????????????????????????? ???????????????????
??????????????????,???????????,??????
??????????(2009?)
32
?????(HEV71)?????

• 30nm
• ??????
• ???

Courtesy of Linda M. Stannard, University of Cape
Town, S.A.h
33
HFMD???????

• ?? HFMD??20?????????,????????????
  ?????????????CoxA??16?4?5?7?9?10??, CoxB??2?5??,
  ?CoxA16 ?EV71?????
• ???? ?-????? ?????
• ????? ????
• ????
• ?????????,??????????
• HFMD???????,????5???????, ?????? ?,????????,
  ???EV71?????????????, ?????????????

34
CoxA16

• 1957?????????,???Seddon?1957???????,1958????Robins
  on????????????CoxA16,?????????????,????CoxA16?????
  
• 1959???HFMD??,HFMD???????,?????????
• ??, ??, ????, ??????????????????
• ?????
• ???1?

35
????71?(enterovirus 71,EV71)
1972?EV71????????,1974?Schmidt??????????????20????
?????????(19691973?)????EV71? ??,?????????EV71??
????EV71?????HFMD???????????????????????????,?????
????????????????,EV71????????????????,????????????
??(acute flaccid paralysis,AFP)????????(non-polio
enterovirus,NPEV)? EV71??????3-7?,??EV71?,????12
??????????,?????????????35?? ?????????,??????????

36
36
?. ????
?????
?????
????
????
?????
?????
????
37
????????

• ?????????????????????
• ????????????,??????????
• ????????????,???????????
• ????????????
• ??????????????????????,?
• ??????
• ????????????????,???????
• ??????,?????
• ???????????????
• ???????,???????????????,
• ????????2-4?????

38
???

• RD??,???????????
• HEp-2??,??????????
• Vero??,??????????
• ?????RD?HEp-2,??RD?Vero?????????????
• ????RD?HEp-2?Vero??,?????????????

39
Progression of CPE EV71 in RD-A Cell
lines EV71?RD-A??????????
40
(No Transcript)
41
??HFMD?????????????

• HFMD????????????????
• ???????,??
• ????????
• ?????????EV71?CVA16V RT-PCR??
• EV71?CVA16 ?Real-time PCR??
• EV71?CVA16 VP1???RT-PCR??
• ?RD/HEp-2????EV71?CVA16
• EV71-IgM?????
• ?????HFMD???????????
• ?? 2008?4?????,12????,2009?7????????
• ?HFMD??????????2009?4?7-10??????????
• ??????????????,2010???HFMD????????

42
?????????????
1 ?????
31??????
????????
43
???????????????
44
???????????
HFMD????????????????
????HFMD????

• ??RT-PCR ???????????
• ?????RT-PCRVP1??
• ?RD/HeP2????????????(SOP)
• ???????????????????????
• ???????????(LAMP)??EV71?CA16??
• nRT-PCR????????EV71?CVA16???????
• rRT-PCR???????????
• rRT-PCR???????EV71??
• rRT-PCR???????CA16??
• rRT-PCR????????????EV71??
• rRT-PCR???????EV71???CA16??
• rRT-PCR????????????EV71???CA16??
• EV71?CA16??????????(????????)
• ???????????????????

??????????????????ELISA?????EV71-IgM?????????????
??
?????????HFMD??????????,??????????????????????HFMD
?????????????
45
???????

• ??????
• ???????
• ??RT-PCR
• ????RT-PCR
• ?????
• ???/???????????
• ELISA?????IgM?IgG

46
??????????
????????????????????????????????????????????????
???? ?????????????????,????????????????????,?????
???????????? ???????????????RD?HEp-2?Vero?,??????
??????????????????????
47
????

• 31???????????????????
• ?????????????????
• ????????????????????
• ????(?????)
• ????(?????)
• ??????????
• ??????????????
• ????

48
????

• ??????????
• ????????
• (????????????RD,HeP2?)
• ???(????)???
• ??????????????????
• ????
• ?????????
• ????3-6????
• ????(???)
• ??????(SOP)
• ???
• ?????????
• PCR,RT-PCR,Real time PCR
• ??
• ?????????
• ????????
• ?????????????

49
??????????????
gt ???? - ?????????? - ?????????? -
?????????? - ?????????? - ?????? -
??????? - ??
gt rRT-PCR????? - ??????????? - ???????? -
????????? - ?????? - ??????????? - ???????
- ??
50
????????
????(HEV71,CA16)
?????
??????
?????,??37.5?, ??????, ????????????????
?????? B19

??? ??????(???)
??
??
51
????????????
???? ?????? ???? ????
Relative levels of antibody

• ??IgM??????????????????????,?????28????
• ?????????,???5??????????

52
?. ????HFMD????????

• 1981?,??????????HFMD??
• 1987???????EV71
• ????????????????Cox A16????,EV 71???Cox
  A16??????,?????????????
• ??80????????????Cox A16??1998??,????????????EV71?
  ?Cox A16????????????
• 1995???,?????????????????????????HFMD??????EV71???
  
• 2007?,?????????????,????HFMD??39,606?,??14????????
  ?????EV71???????HFMD?????,??????Echo3 ?/? CVA16?
• 2008?- 2010?7???????CoxA16 ?EV71 ???????????,
  ?????EV71???????, ???CoxA16 ?????,????????????????
  ????

53
????HFMD??
1997 Malaysia 34 deaths
1998 Taiwan 78 deaths
1998 Various 4 deaths
1999 Australia 29 severe cases
1999 Taiwan 9 deaths
2000 Singapore 7 deaths
2000 Taiwan 41 deaths
2000 Malaysia 4 deaths
2000 Japan HFMD epidemic
2000 Canada City outbreaks
2001 Taiwan 58 deaths
2001 Australia 44 severe cases
2002 Taiwan 30 deaths
2003 Malaysia HFMD epidemic
2003 Taiwan 8 deaths
2003 China (Macao) at least 1 death
2003 China (Beijing) gt5cases/day
2004 Taiwan 5 deaths
2004 USA City outbreak of HFMD
2004 UK Schools closed
2005 Singapore 15247 HFMD cases
2006 Malaysia Schools Playgrounds closed for 2 weeks
2006 Singapore gt15000 cases with school closures
2007 China gt80,000 cases, 17 deaths
2007 Singapore gt20,000 cases
2008 Singapore gt17,000 cases to date with school closures
2008 Taiwan 200,000 cases, 10 deaths confirmed (17)
2008 China gt175,000 cases, 44 deaths
2008 Vietnam gt 2,000 cases?, 11 deaths
JAPAN
CHINA
INDIA
Taiwan
BURMA
Hong Kong
LAOS
VIETNAM
THAILAND
PHILIPPINES
CAMBODIA
Palawan
Brunei
MALAYSIA
Halmahera
Borneo
New Guinea
SINGAPORE
INDONESIA
Java
Bali
Sumba
AUSTRALIA
54
EV71???????/????????????
??? ???? ????
A ?? 1970
B1 ???????????????????????? 19721987
B2 ??? 19811987
B3 ????????????? 19971999
B4 ???????????????? 19972002
B5 ???? 2003
C1 ????????????????????????? 19862005
C2 ???????????????? 19952002
C3 ????? 1997?2003
C4 ????????????? 19982007
C5 ?? 2005
55
????????????
??????????????

• 2008???489073?
• ????37.01/100,000
• ????1165? ,??????? 0.24
• ??126?,??? 0.26

56
2008????????????????
??????????????
57
2008??????????????????
??????????????
58
2010?????????

• ???

• ???

59
2010???????????????????
???? ????
??? 22975 781
????? 1.91 1.97
3????() 82.04 88.97
5????() 96.64 98.59
???? ??1? 1??
???? 31? 10?
60

• ?. HFMD ????
• ????2008?-2010?8?15?

61
??????????????(2008)
???

• ????(1165?)
• EV71 ? ????
• ???????
• 81.59

• ????(126?)
• EV71 ? ????
• ???????
• 96.43

62
????2008?HFMD ???? Viral etiology of HFMD in
China
?1. HFMD????????????????? Table1A
. Isolation rate of HEV from Clinical samples of
HFMD Cases
samples HEV71 CVA16 Others
4,769 790 (16.6) 214 (4.5) 75 (1.6)
?2. HFMD???????????PCR??????
Table1B. PCR positive rate of hev from Clinical
samples of HFMD Cases
samples HEV71 CVA16 Others
18,153 4,636(25.5) 1,092 (6.0) 1740 (9.6)
63
???????HFMD?????
???
2009?
?? ??? ??? ??? ??? ??? () EV71() CoxA16() ??? ???()
???? 1141792 19351 1.70 40.63 37.55 21.82
???? 13811 4133 29.92 80.60 4.61 14.80
???? 354 222 62.72 92.80 1.36 5.86
2010?
?? ??? ??? ??? ??? ??? () EV71() CoxA16() ??? ???()
???? 1775105 63624 3.59 52.66 27.82 19.51
???? 27915 13282 48.84 81.6 3.75 14.6
???? 905 645 71.27 92.40 0.78 6.82
????????????????????EV71??
64
2010???????????????????
?? ?? ??? ?????? ?????? () EV71???() ??EV??? ()
???? 4290 20 0.47 75 25
???? 302 86 28.48 72.09 27.91
???? 10 10 100 80 20

• ????????HFMD106?,????????2.31,??EV71??77?,???????
  ??72.64,??EV??29?,?????????27.36??????,EV71??62?
  ,???????????72.09

64
65
??????-????HFMD?????
Group 1 Group 1
?????? ??????
?????? 153
EV71-S\A 263
CoxA 16-S\A 245
CA12 163
CB4 167
CB5 193
CA16 203
CB1 223
CB2 233
CA6 243
CA9 251
CA10 273
CB3 282
CA24 296
CA4 256
66
???????????????????
67
??HFMD????????????
?????????,???EV71???????,???
??HFMD???????????????????????

• 1998????????????,?48.7??????75??????92?????????
  HEV71?
• 2. 2007??????????????,?8?????,???????????,HEV71??8
  4,CVA16??162008?????????????,???????????,??????
  CVA16??(?62),???????????
• 3. 2008????????99????HEV71???
• 4. 2009??????????HEV71?????
• 5. 2010?????HEV71?????

68

• ?. ???????????????

69
EV71???

• ????()ssRNA,
• ???7400nt
• ??????,??
• ?11???
• ??,VP1VP4??
• ???????

• VP1???????????,?????????????,VP1??????(891nt)???EV
  ????????????
• ?VP1????,??????VP4?VP2????????5'NTR????????VP1????
  ?????????????????????,??EV?????????
• ???????????????(ORF),???????,???????????,?????????
  4??????7??????,????????4?????????

70
EV71???????????? Target gene used for EV71
molecular epidemiology
1999?,Brown???19701998?????????5????113?EV71?VP1?
????,?EV71??????????,???A?B?C???,?????????lt12,???
??16.519.7? ???????,??????????????????B1-B5,C
1-C5
71
EV71?????/???????????? Geographic and time
distribution of all genotype/subgenotype of EV71
???/??Genotype /subgenotype ????/?? Country/district ???? Year
A ?? 1970
B1 ???????????????????????? 19721987
B2 ??? 19811987
B3 ????????????? 19971999
B4 ???????????????? 19972002
B5 ??????????????? 20032008
C1 ??????????????????????????????? 19862005
C2 ????????????????????? 19952008
C3 ????? 1997?2003
C4 ???????????????????????????,?? 19982010
C5 ??????? 20052007
72
Genotype of EV71 Circulating in global from
19702009 19702009???EV71??????
Genotypes still circulate in Asia-Pacific region.
73
??????-1
????????????????????????
????????????EV71?CA16???????
VP1
Whole genome
3D
? fatal cases ? mild ? severe.
74
??????-2
???????C4???????????

• 19982010,1998???????HEV71??????C4????,??HEV71
  C4???????????????12????
• ??????C4??????? C4a?C4b,C4a??2002?????C4b??200
  4??????
• C4a?C4b????6.7,???????2.8? 5.0????????3.4.
• 2007-2010?????????????

-2010
75
CA16???????

• ??,CA16???A, B?????,B???????B1?B2?????
• A?????????G-10,?B??????VP1????? 27.5 - 30.2?
• B1?B2????VP1?????11.8
• ??1999???CA16????B1???

76
??????-3
CA16?????????1997-2010

• ????? ?CA16?B1??,???B1a?B1b?B1c,???CA16??????????
  ??????????????

77
?????-1
?????????????????(2005)
??????
??????????????? ??????????????, ????????EV71???? ?
?,??????????
EV71
CA16
78
???????????
79

• ?. HFMD??????

80
HFMD????

• ????????????????
• ???????????
• ???????????????????

81
????????????

• ???????,????????
• ???????????
• ???????????,??????
• ????????????????,??????

82
????

• ????
• ???????????
• ????????
• ?????????,?????????????????,????????
• ??????????,???????
• ????????????,??????????
• ????????
• ?????????????????
• ??????ICU???
• ????????,???????

83
????(?)

• ????????????????
• ?????????????
• ????????????
• ????????(???????)
• ????????????????????
• ?????????????
• ??????,????????
• ?????????????
• ???????????????
• ????????

84
84
Acknowledgement ??
?????????????? ????????? ???????????????? ?????
85
THANK YOU!