淋球菌的免疫逃避
（淋球菌利用（剥削）宿主的先天免疫）
Immune evasion of Neisseria gonorrhoeae
华中科技大学同济医学院附属同济医院
陈铁
Tie Chen, M.D. Professor
Tongji Hospital
Tongji Medical College
Huazhong University of Science and Technology
Visiting Associate Professor
Indiana University School of Medicine
N. gonorrhoeae, (gonococci, GC, the cause of gonorrhea)
奈氏淋球菌
Gonococci Invade Host Cells
淋球菌侵入属主细胞
Some Facts about Neisseria gonorrhoeae
(gonococci, GC)
1. Genital Infection:
gonorrhea
2. Cervical- pelvic
inflammatory disease (PID)
3. Pharyngeal, Rectal
Infection, eye
and systemic spread
5. 78 million cases each year.
6. It is an ancient disease.
古老的疾病
7. No animal model
没有动物模型
8. Does not generate
protective immune response
不产生保护性免疫
4. Other noted names:
9. Ability to facilitate HIV
Clap, Flowing seeds, Happy
infection?
disease and Mother of STD
能促进HIV的感染
GC Forms Opaque Colonies
Opa Protein Expression
Interaction of Neisseria gonorrhoeae with Host Cells
奈氏淋球菌与宿主细胞的相互作用
1. Initial adherence
初期粘附
2. Tight adherence
紧密粘附
3. Invasion/uptake
侵袭/吞噬
4. Transcytosis
胞吞转运
1. Neisseria gonorrhoeae inhibits host responses.
证明CEA(CD66, carcinoembryonic antigen)抗
原是奈氏淋球菌的受体
R.J. Belland*, T. Chen, J. Swanson and S.H. Fischer. 1992.
Mol. Microbiol. 6:1729-1737.
T. Chen, R. Belland, J. Wilson, and J. Swanson*. 1995.
J. Exp. Med. 182:511-517.
T. Chen, J. Swanson, J. Wilson, and R. Belland*. 1995.
Infect. Immun. 63:1790-1795.
T. Chen* and E. Gotschlich. 1996.
Proc. Natl. Acad. Sci. USA. 93:14851-14856.
T. Chen*, F. Grunert, A. Medina-Marino and E. C. Gotschlich. 1997.
J. Exp. Med. 185:1557-1564.
CEA (CEACAM, CD66, carcinoembryonic antigen)
Ag Serve as Receptors for Opa+ GC
CEA(CD66)抗原是奈氏淋球菌的受体
CEACAM1, (BGPa
CD66a)CEACAM8 CEACAM6
CEACAM3, (CGM1a,
CD66d)
Inhibition ITIM 阴 ITAM Activation
阳
Extracellular
Membrane
Cytoplasmic
阳性和阴性的信号传递
?
BTK
抑制 抗体产生
T. Chen*, W. Zimmermann, J. Parker, I. Chen, A. Maeda and S. Bolland. 2001
J. Leuko. Biol. 70:335-340.
T. Chen*, S. Bolland, I. Chen, J. Parker, M. Pantelic, F. Grunert, and W.
Zimmermann. 2001. J. Biol. Chem. 276:17413-17419.
Potential ITAM or ITIM Motif in the
Cytoplasmic Domain Of BGPa and CGM1a
Immunoreceptor Tyrosine-based Activation ( or Inhibition)
Motif
ITAM
ITIM
BGPa
CGM1a
(CD66d)
D/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I
V/IxYxxL
DPPNKMNEVTYSTLNFEAQQPTQPTSASPSLTATEIIYSEV
(CD66a)
(may contain ITAM)
PLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS
(may contain ITAM)
Construction of CGM1a (CD66d)-Tyrosine Mutants
ITAM
CGM1a
D/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I
PLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS
|
Y207
|
Y196
CGM1a Contains a Functional ITAM
109.4
100
90
DT40-CGM1a
80
OpaI GC
[Ca++] 70
[CA++]
60
50
CGM1a-Y196F
40
CGM1a-Y207F
CGM1a-Y196F/Y207F
25.4
1.9
100
200
300
S
400
Time, seconds
500
DT40
604.2
B-Cell
阳性和阴性的信号传递
?
BTK
抑制 抗体产生
T. Chen*, W. Zimmermann, J. Parker, I. Chen, A. Maeda and S. Bolland. 2001
J. Leuko. Biol. 70:335-340.
T. Chen*, S. Bolland, I. Chen, J. Parker, M. Pantelic, F. Grunert, and W.
Zimmermann. 2001. J. Biol. Chem. 276:17413-17419.
Assay of Inhibition by ITIM
a-BCR MAb (A)
(stimulates ITAM)
a-Mouse Ab (I)
(stimulates ITIM)
B Cell
Receptor
(BCR)
FcgRIIB-BGPa
Fc(RIIB-BGPa Chimeric Molecules
Extrace llular
Fc(RIIB
TM
C ytoplasm ic
BGPa
FcgRIIB-BGP
(W T)
FcgRIIB-BGP
(Y459F)
Y459F
FcgRIIB-BGP
(Y486F)
Y486F
FcgRIIB-BGP
(Y459-486F)
Y459F
Y486F
Flow C ytom e try
Y459 is Essential for Inhibiting Ca++ Influx
14 6.6
Fc(RIIB-BGPa
Fc(RIIB-BGPa-Y459F
19 1.6
12 0
10 0
I
A
15 0
80
[C A++]
60
I
A
10 0
[C A++]
40
50
20
3. 2
1. 9
-7 .1
50
10 0
15 0
S
20 0
25 0 30 2.1
1. 9
50
Fc(RIIB-BGPa-Y486F
13 6.4
12 0
10 0
10 0
15 0
S
20 0
25 0 30 2.1
Fc(RIIB-BGPa-Y459/486F
17 3.7
16 0
I
A
14 0
12 0
80
I
A
10 0
[C A++]60
[C A++] 80
60
40
40
20
20
0. 0
1. 9
50
10 0
15 0
S
20 0
25 0 30 2.1
0. 4
1. 9
50
10 0
15 0
S
20 0
25 0
30 4.0
Hypothesis:
The interactions of GC with CEACAM on
neutrophils （白血球） or B cells shape
host responses.
No. bact
阳性信号传递导致细胞死亡
CEACAM3 (CD66d) Controls Cell Death.
Control
Opa- GC
OpaI GC
80
60
40
20
7F
7F
20
20
Y
19
6F
/Y
Y
6F
19
C
A
E
C
Y
A
T
M
40
3
0
D
cell death
Cell Death %
100
阴性的信号传递抑制 抗体产生
Human Ig (µg/ml)
GC Inhibits Antibody Production by Primary Human B Cells
Summary:
Neisseria gonorrhoeae inhibits host responses
of CEACAM-expressing host cells through
either activating or inhibitory signal
transduction.
奈氏淋球菌借助了人体的阴性/阳性的信号转导过程，抑
制了人体的免疫反应