1. 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. Professor Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Visiting Associate Professor Indiana University School of Medicine 华中科技大学同济医学院附属同济医院 陈铁

2. N. gonorrhoeae, (gonococci, GC, the cause of gonorrhea) 奈氏淋球菌

3. Gonococci Invade Host Cells 淋球菌侵入属主细胞

4. 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 4. Other noted names: Clap, Flowing seeds, Happy disease 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

5. GC Forms Opaque Colonies

6. Opa Protein Expression

8. 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

9. 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.

10. CEA (CEACAM, CD66, carcinoembryonic antigen) Ag Serve as Receptors for Opa + GC CEACAM1, (BGPa CD66a) CEACAM3, (CGM1a, CD66d) Membrane Extracellular Cytoplasmic CEACAM6CEACAM8 ITAM ITIM Activation Inhibition CEA(CD66) 抗原是奈氏淋球菌的受体 阳 阴

11. ? 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

12. 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 D PPNKMN EV T Y ST L NFEAQQPTQPTSASPSLTATEII Y SEV (CD66a) (may contain ITAM) CGM1a PLPNPRTAASI Y EE L LKHDTNI Y CR M DHKAVAS (CD66d) (may contain ITAM)

13. Construction of CGM1a (CD66d)-Tyrosine Mutants ITAM D/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I CGM1a PLPNPRTAASI Y EE L LKHDTNI Y CR M DHKAVAS | | Y207 Y196

14. CGM1a Contains a Functional ITAM OpaI GC DT40-CGM1a Time, seconds [Ca++]

15. ? 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

16. Assay of Inhibition by ITIM  -BCR MAb (A) (stimulates ITAM) B Cell Receptor (BCR)  -Mouse Ab (I) (stimulates ITIM) Fc  RIIB-BGPa

17. Fc ( RIIB-BGPa Chimeric Molecules Fc ( RIIB BGPa

18. Y459 is Essential for Inhibiting Ca++ Influx Fc ( RIIB-BGPaFc ( RIIB-BGPa-Y459F Fc ( RIIB-BGPa-Y486FFc ( RIIB-BGPa-Y459/486F A A A A I I I I

19. Hypothesis: The interactions of GC with CEACAM on neutrophils （白血球） or B cells shape host responses.

20. No. bacteria/well 10 -2 DT40-cell Y207FY196F CEACAM1 phagocytosis cell death CEACAM3 (CD66d) Controls Cell Death. 阳性信号传递导致细胞死亡

21. Human Ig (µg/ml) stimulators + Opa- GC stimulators + OpaI GC no stimulators stimulators GC Inhibits Antibody Production by Primary Human B Cells 阴性的信号传递抑制 抗体产生

22. 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