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Immune evasion of Neisseria gonorrhoeae

Immune evasion of Neisseria gonorrhoeae

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Immune evasion of Neisseria gonorrhoeae

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  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) 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

  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 5. 78 million cases each year. 6. It is an ancient disease. 古老的疾病 2. Cervical- pelvic inflammatory disease (PID) 7. No animal model 没有动物模型 3. Pharyngeal, Rectal Infection, eye and systemic spread 4. Other noted names: Clap, Flowing seeds, Happy disease and Mother of STD 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

  7. 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

  8. 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.

  9. 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) Extracellular Membrane 阴 Inhibition ITIM 阳 Cytoplasmic ITAM Activation

  10. 阳性和阴性的信号传递 ? 抑制 抗体产生 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.

  11. 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 • ITIMV/IxYxxL • BGPaDPPNKMNEVTYSTLNFEAQQPTQPTSASPSLTATEIIYSEV • (CD66a) (may contain ITAM) • CGM1aPLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS • (CD66d) (may contain ITAM)

  12. Construction of CGM1a (CD66d)-Tyrosine Mutants • ITAMD/ExxxxxxxD/ExxYxxLxxxxxxxYxxL/I • CGM1aPLPNPRTAASIYEELLKHDTNIYCRMDHKAVAS | | Y207 Y196

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

  14. 阳性和阴性的信号传递 ? 抑制 抗体产生 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.

  15. a-BCR MAb (A) (stimulates ITAM) a-Mouse Ab (I) (stimulates ITIM) B Cell Receptor (BCR) FcgRIIB-BGPa Assay of Inhibition by ITIM

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

  17. Y459 is Essential for Inhibiting Ca++ Influx Fc(RIIB-BGPa Fc(RIIB-BGPa-Y459F I A I A Fc(RIIB-BGPa-Y486F Fc(RIIB-BGPa-Y459/486F I A I A

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

  19. phagocytosis No. bacteria/well 10-2 Y196F Y207F DT40-cell CEACAM1 cell death 阳性信号传递导致细胞死亡 CEACAM3 (CD66d) Controls Cell Death.

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

  21. 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