Immune evasion of Neisseria gonorrhoeae
淋球菌的免疫逃避(淋球菌利用(剥削)宿主的先天免疫)
Tie Chen, M.D. ProfessorTongji Hospital
Tongji Medical CollegeHuazhong University of Science and Technology
Visiting Associate ProfessorIndiana University School of Medicine
华中科技大学同济医学院附属同济医院陈铁
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- pelvicinflammatory disease (PID)
3. Pharyngeal, Rectal Infection, eye and systemic spread
4. Other noted names:Clap, Flowing seeds, Happydisease and Mother of STD
6. It is an ancient disease. 古老的疾病
5. 78 million cases each year.
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9. Ability to facilitate HIV infection?能促进 HIV 的感染
GC Forms Opaque Colonies
Opa Protein Expression
Interaction of Neisseria gonorrhoeae with Host Cells
1. Initial adherence
2. Tight adherence
3. Invasion/uptake
4. Transcytosis
奈氏淋球菌与宿主细胞的相互作用
初期粘附
紧密粘附
侵袭 / 吞噬
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
.
s
s
s
s
s
s
s
s
s
s
s
s
s
s
N
s
s
s
s
s
s
s
sN
s
s
s
s
s
sN
s
s
s
s
s
sN
s
sN
s
s
s
s
s
s
s
sN
BGPa
CGM6
CGM1a
NCA
CEA
PSG1
Plasmic membrane
Cytoplasmic domain
E x t r a c e l l u l a r D o m a i n
GPI linkageB1
A1
A1A1
A1
B1B2
B1
B1
A1
B2A2
A2
A2 B3
A3
CEA (CD66) Family Antigens
(CD66a)
(CD66b) (CD66c)
(CD66d)
(CD66e)
(CD66f)CEACAM1, (BGPa CD66a)
CEACAM3, (CGM1a,CD66d)
MembraneExtracellular
Cytoplasmic
CEACAM6CEACAM8
ITAMITIM ActivationInhibition
CEA(CD66) 抗原是奈氏淋球菌的受体
阳阴
PP
B Cellreceptor
PTKs
INTERNALIZATION
ITAM
ss
PP
CEACAM3 (CD66d)
ss
ss
ss
ss
PP
SHP-1SHIP
SHP-2
ITIM
CEACAM1 (CD66a)
Activation Versus Inhibition
PROLIFERATION
GC
ANTIBODY PRODUCTION
GC
PLC
Ca2+
Ca2+
P
FcRIIB
APOPTOSIS
Extracellular
Intracellular
?
BTK
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.
阳性和阴性的信号传递
抑制 抗体产生
Potential ITAM or ITIM Motif in the Cytoplasmic Domain Of BGPa and CGM1a
Immunoreceptor Tyrosine-based Activation ( or Inhibition) Motif
ITAM D/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I ITIM V/IxYxxL
BGPa DPPNKMNEVTYSTLNFEAQQPTQPTSASPSLTATEIIYSEV (CD66a) (may contain ITAM)
CGM1a PLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS (CD66d) (may contain ITAM)
Extracellular Cytoplasmic
Y196F
Y207F
Y207FY196F
TM
CGM1a
CGM1a-Y207F
CGM1a-Y196F/Y207F
CGM1a-Y196F
Construction of CGM1a (CD66d)-Tyrosine Mutants
ITAM D/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I CGM1a PLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS
| |Y207 Y196
CGM1a Contains a Functional ITAM
OpaI GC
1.9 100 200 300 400 500 604.2
25.4
40
50
60
70
80
90
100
109.4
S
[CA++]
DT40-CGM1a
CGM1a-Y196F
CGM1a-Y207F
DT40 B-Cell
CGM1a-Y196F/Y207F
Time, seconds
[Ca++]
PP
B Cellreceptor
PTKs
INTERNALIZATION
ITAM
ss
PP
CEACAM3 (CD66d)
ss
ss
ss
ss
PP
SHP-1SHIP
SHP-2
ITIM
CEACAM1 (CD66a)
Activation Versus Inhibition
PROLIFERATION
GC
ANTIBODY PRODUCTION
GC
PLC
Ca2+
Ca2+
P
FcRIIB
APOPTOSIS
Extracellular
Intracellular
?
BTK
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.
阳性和阴性的信号传递
抑制 抗体产生
Assay of Inhibition by ITIM
FcRIIB-BGPa
Primary antibody
Secondary antibody IgM
PP
B cellreceptor (BCR)
IT A M PP
IT IM
-BCR MAb (A)(stimulates ITAM)
B CellReceptor(BCR)
-Mouse Ab (I)(stimulates ITIM)
FcRIIB-BGPa
FcRIIB-BGP (WT)
FcRIIB-BGP (Y459F)
FcRIIB-BGP (Y486F)
FcRIIB-BGP (Y459-486F)
Extracellular Cytoplasmic
Y459F
Y486F
Y486FY459F
Flow CytometryTM
FcRIIB-BGPa Chimeric Molecules
FcRIIB BGPa
1.9 50 100 150 200 250 302.13.2
20
40
60
80
100
120
146.6
S
[CA++]
1.9 50 100 150 200 250 302.1
-7.1
50
100
150
191.6
S
[CA++]
1.9 50 100 150 200 250 302.1
0.0
20
40
60
80
100
120
136.4
S
[CA++]
1.9 50 100 150 200 250 304.0
0.4
20
40
60
80
100
120
140
160173.7
S
[CA++]
Y459 is Essential for Inhibiting Ca++ Influx
FcRIIB-BGPa FcRIIB-BGPa-Y459F
FcRIIB-BGPa-Y486F FcRIIB-BGPa-Y459/486F
A A
AA
I I
II
Hypothesis: The interactions of GC with CEACAM on
neutrophils (白血球) or B cells shape host responses.
.
0
200
400
600
800
1000
1200
0
20
40
60
80
100
ControlOpa- GCOpaI GC
No.
bac
teri
a/w
ell 1
0-2
DT40-ce
ll
Y207F
Y196F
CEACAM1
0
20
40
60
80
100
ControlOpa- GCOpaIGC
phagocytosis
cell death
CEACAM3 (CD66d) Controls Cell Death.
阳性信号传递导致细胞死亡
Hu
man
Ig
(µg/
ml)
stim
ulator
s + O
pa- G
C
stim
ulator
s + O
paI G
C0.00
0.10
0.20
0.30
0.40
0.50
0.60
no stim
ulator
s
stim
ulator
s
GC Inhibits Antibody Production by Primary Human B Cells
阴性的信号传递抑制 抗体产生
Neisseria gonorrhoeae inhibits host responses of CEACAM-expressing host cells through either activating or inhibitory signal transduction.
Summary:
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
Top Related