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. 1997 Sep;65(9):3736–3742. doi: 10.1128/iai.65.9.3736-3742.1997

A proposed role for the lutropin receptor in contact-inducible gonococcal invasion of Hec1B cells.

J M Spence 1, J C Chen 1, V L Clark 1
PMCID: PMC175533  PMID: 9284146

Abstract

We previously reported the existence of a contact-inducible, enhanced invasion phenotype in the obligate human pathogen Neisseria gonorrhoeae. Our present studies showed that the ability of glutaraldehyde-fixed eucaryotic cells to convert gonococci (GC) to this invasive phenotype (Inv+) is limited to cells derived from reproductive tissues. We present evidence that GC recognize the lutropin receptor (LHr), which recognizes both luteinizing hormone and human chorionic gonadotropin (hCG), as the tissue-specific environmental signal that induces the conversion of GC to the Inv+ phenotype. By competitive binding studies, we showed that Inv+ GC bind to Hec1B cells, a human endometrial cell line, by a unique adhesin not present on noninduced GC and that this Inv+ GC-specific binding is completely blocked by the addition of hCG. We demonstrated that limiting the access of GC to LHr decreases the ability of the host cell to both convert GC to the Inv+ phenotype and serve as a target for Inv+ GC invasion. We propose a model of GC invasion of Hec1B cells in which the LHr plays a dual role both as an induction signal and as part of the internalization mechanism. This utilization of LHr could account for both the preponderance of complicated GC disease in women and the observed correlation of the disease with the onset of menses.

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Selected References

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  1. Barnes R. C., Holmes K. K. Epidemiology of gonorrhea: current perspectives. Epidemiol Rev. 1984;6:1–30. doi: 10.1093/oxfordjournals.epirev.a036267. [DOI] [PubMed] [Google Scholar]
  2. Bessen D., Gotschlich E. C. Interactions of gonococci with HeLa cells: attachment, detachment, replication, penetration, and the role of protein II. Infect Immun. 1986 Oct;54(1):154–160. doi: 10.1128/iai.54.1.154-160.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bliska J. B., Galán J. E., Falkow S. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell. 1993 Jun 4;73(5):903–920. doi: 10.1016/0092-8674(93)90270-z. [DOI] [PubMed] [Google Scholar]
  4. Chen J. C., Bavoil P., Clark V. L. Enhancement of the invasive ability of Neisseria gonorrhoeae by contact with HecIB, an adenocarcinoma endometrial cell line. Mol Microbiol. 1991 Jun;5(6):1531–1538. doi: 10.1111/j.1365-2958.1991.tb00800.x. [DOI] [PubMed] [Google Scholar]
  5. Chen T., Gotschlich E. C. CGM1a antigen of neutrophils, a receptor of gonococcal opacity proteins. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14851–14856. doi: 10.1073/pnas.93.25.14851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cruz R. I., Anderson D. M., Armstrong E. G., Moyle W. R. Nonreceptor binding of human chorionic gonadotropin (hCG): detection of hCG or a related molecule bound to endometrial tissue during pregnancy using labeled monoclonal antibodies that bind to exposed epitopes on the hormone. J Clin Endocrinol Metab. 1987 Mar;64(3):433–440. doi: 10.1210/jcem-64-3-433. [DOI] [PubMed] [Google Scholar]
  7. Eschenbach D. A., Holmes K. K. The etiology of acute pelvic inflammatory disease. Sex Transm Dis. 1979 Jul-Sep;6(3):224–227. doi: 10.1097/00007435-197907000-00010. [DOI] [PubMed] [Google Scholar]
  8. Falkow S. Bacterial entry into eukaryotic cells. Cell. 1991 Jun 28;65(7):1099–1102. doi: 10.1016/0092-8674(91)90003-h. [DOI] [PubMed] [Google Scholar]
  9. Falkow S., Isberg R. R., Portnoy D. A. The interaction of bacteria with mammalian cells. Annu Rev Cell Biol. 1992;8:333–363. doi: 10.1146/annurev.cb.08.110192.002001. [DOI] [PubMed] [Google Scholar]
  10. Finlay B. B., Falkow S. Common themes in microbial pathogenicity. Microbiol Rev. 1989 Jun;53(2):210–230. doi: 10.1128/mr.53.2.210-230.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ghinea N., Mai T. V., Groyer-Picard M. T., Milgrom E. How protein hormones reach their target cells. Receptor-mediated transcytosis of hCG through endothelial cells. J Cell Biol. 1994 Apr;125(1):87–97. doi: 10.1083/jcb.125.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gorby G. L., Clemens C. M., Barley L. R., McGee Z. A. Effect of human chorionic gonadotropin (hCG) on Neisseria gonorrhoeae invasion of and IgA secretion by human fallopian tube mucosa. Microb Pathog. 1991 May;10(5):373–384. doi: 10.1016/0882-4010(91)90082-l. [DOI] [PubMed] [Google Scholar]
  13. Grassmé H. U., Ireland R. M., van Putten J. P. Gonococcal opacity protein promotes bacterial entry-associated rearrangements of the epithelial cell actin cytoskeleton. Infect Immun. 1996 May;64(5):1621–1630. doi: 10.1128/iai.64.5.1621-1630.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hoffman Y. M., Peegel H., Sprock M. J., Zhang Q. Y., Menon K. M. Evidence that human chorionic gonadotropin/luteinizing hormone receptor down-regulation involves decreased levels of receptor messenger ribonucleic acid. Endocrinology. 1991 Jan;128(1):388–393. doi: 10.1210/endo-128-1-388. [DOI] [PubMed] [Google Scholar]
  15. Jonsson A. B., Ilver D., Falk P., Pepose J., Normark S. Sequence changes in the pilus subunit lead to tropism variation of Neisseria gonorrhoeae to human tissue. Mol Microbiol. 1994 Aug;13(3):403–416. doi: 10.1111/j.1365-2958.1994.tb00435.x. [DOI] [PubMed] [Google Scholar]
  16. KELLOGG D. S., Jr, PEACOCK W. L., Jr, DEACON W. E., BROWN L., PIRKLE D. I. NEISSERIA GONORRHOEAE. I. VIRULENCE GENETICALLY LINKED TO CLONAL VARIATION. J Bacteriol. 1963 Jun;85:1274–1279. doi: 10.1128/jb.85.6.1274-1279.1963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kahrs A. F., Bihlmaier A., Facius D., Meyer T. F. Generalized transposon shuttle mutagenesis in Neisseria gonorrhoeae: a method for isolating epithelial cell invasion-defective mutants. Mol Microbiol. 1994 Jun;12(5):819–831. doi: 10.1111/j.1365-2958.1994.tb01068.x. [DOI] [PubMed] [Google Scholar]
  18. LaPolt P. S., Jia X. C., Sincich C., Hsueh A. J. Ligand-induced down-regulation of testicular and ovarian luteinizing hormone (LH) receptors is preceded by tissue-specific inhibition of alternatively processed LH receptor transcripts. Mol Endocrinol. 1991 Mar;5(3):397–403. doi: 10.1210/mend-5-3-397. [DOI] [PubMed] [Google Scholar]
  19. Lei Z. M., Toth P., Rao C. V., Pridham D. Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes. J Clin Endocrinol Metab. 1993 Sep;77(3):863–872. doi: 10.1210/jcem.77.3.7690366. [DOI] [PubMed] [Google Scholar]
  20. Lin J., Lei Z. M., Lojun S., Rao C. V., Satyaswaroop P. G., Day T. G. Increased expression of luteinizing hormone/human chorionic gonadotropin receptor gene in human endometrial carcinomas. J Clin Endocrinol Metab. 1994 Nov;79(5):1483–1491. doi: 10.1210/jcem.79.5.7962347. [DOI] [PubMed] [Google Scholar]
  21. Lloyd C. E., Ascoli M. On the mechanisms involved in the regulation of the cell-surface receptors for human choriogonadotropin and mouse epidermal growth factor in cultured Leydig tumor cells. J Cell Biol. 1983 Feb;96(2):521–526. doi: 10.1083/jcb.96.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Makino S., van Putten J. P., Meyer T. F. Phase variation of the opacity outer membrane protein controls invasion by Neisseria gonorrhoeae into human epithelial cells. EMBO J. 1991 Jun;10(6):1307–1315. doi: 10.1002/j.1460-2075.1991.tb07649.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mandrell R. E., Apicella M. A. Lipo-oligosaccharides (LOS) of mucosal pathogens: molecular mimicry and host-modification of LOS. Immunobiology. 1993 Apr;187(3-5):382–402. doi: 10.1016/S0171-2985(11)80352-9. [DOI] [PubMed] [Google Scholar]
  24. Mandrell R. E., Lesse A. J., Sugai J. V., Shero M., Griffiss J. M., Cole J. A., Parsons N. J., Smith H., Morse S. A., Apicella M. A. In vitro and in vivo modification of Neisseria gonorrhoeae lipooligosaccharide epitope structure by sialylation. J Exp Med. 1990 May 1;171(5):1649–1664. doi: 10.1084/jem.171.5.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McGee Z. A., Clemens C. M., Jensen R. L., Klein J. J., Barley L. R., Gorby G. L. Local induction of tumor necrosis factor as a molecular mechanism of mucosal damage by gonococci. Microb Pathog. 1992 May;12(5):333–341. doi: 10.1016/0882-4010(92)90096-7. [DOI] [PubMed] [Google Scholar]
  26. McGee Z. A., Johnson A. P., Taylor-Robinson D. Pathogenic mechanisms of Neisseria gonorrhoeae: observations on damage to human fallopian tubes in organ culture by gonococci of colony type 1 or type 4. J Infect Dis. 1981 Mar;143(3):413–422. doi: 10.1093/infdis/143.3.413. [DOI] [PubMed] [Google Scholar]
  27. Mekalanos J. J. Environmental signals controlling expression of virulence determinants in bacteria. J Bacteriol. 1992 Jan;174(1):1–7. doi: 10.1128/jb.174.1.1-7.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miller J. F., Mekalanos J. J., Falkow S. Coordinate regulation and sensory transduction in the control of bacterial virulence. Science. 1989 Feb 17;243(4893):916–922. doi: 10.1126/science.2537530. [DOI] [PubMed] [Google Scholar]
  29. Mårdh P. A. An overview of infectious agents of salpingitis, their biology, and recent advances in methods of detection. Am J Obstet Gynecol. 1980 Dec 1;138(7 Pt 2):933–951. doi: 10.1016/0002-9378(80)91084-4. [DOI] [PubMed] [Google Scholar]
  30. Nassif X., So M. Interaction of pathogenic neisseriae with nonphagocytic cells. Clin Microbiol Rev. 1995 Jul;8(3):376–388. doi: 10.1128/cmr.8.3.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Parsons N. J., Andrade J. R., Patel P. V., Cole J. A., Smith H. Sialylation of lipopolysaccharide and loss of absorption of bactericidal antibody during conversion of gonococci to serum resistance by cytidine 5'-monophospho-N-acetyl neuraminic acid. Microb Pathog. 1989 Jul;7(1):63–72. doi: 10.1016/0882-4010(89)90112-5. [DOI] [PubMed] [Google Scholar]
  32. Peegel H., Randolph J., Jr, Midgley A. R., Menon K. M. In situ hybridization of luteinizing hormone/human chorionic gonadotropin receptor messenger ribonucleic acid during hormone-induced down-regulation and the subsequent recovery in rat corpus luteum. Endocrinology. 1994 Sep;135(3):1044–1051. doi: 10.1210/endo.135.3.8070346. [DOI] [PubMed] [Google Scholar]
  33. Rebois R. V. Establishment of gonadotropin-responsive murine leydig tumor cell line. J Cell Biol. 1982 Jul;94(1):70–76. doi: 10.1083/jcb.94.1.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rebois R. V., Fishman P. H. Down-regulation of gonadotropin receptors in a murine Leydig tumor cell line. J Biol Chem. 1984 Mar 10;259(5):3096–3101. [PubMed] [Google Scholar]
  35. Reshef E., Lei Z. M., Rao C. V., Pridham D. D., Chegini N., Luborsky J. L. The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua. J Clin Endocrinol Metab. 1990 Feb;70(2):421–430. doi: 10.1210/jcem-70-2-421. [DOI] [PubMed] [Google Scholar]
  36. Rodriguez M. C., Xie Y. B., Wang H., Collison K., Segaloff D. L. Effects of truncations of the cytoplasmic tail of the luteinizing hormone/chorionic gonadotropin receptor on receptor-mediated hormone internalization. Mol Endocrinol. 1992 Mar;6(3):327–336. doi: 10.1210/mend.6.3.1316539. [DOI] [PubMed] [Google Scholar]
  37. Schwan E. T., Robertson B. D., Brade H., van Putten J. P. Gonococcal rfaF mutants express Rd2 chemotype LPS and do not enter epithelial host cells. Mol Microbiol. 1995 Jan;15(2):267–275. doi: 10.1111/j.1365-2958.1995.tb02241.x. [DOI] [PubMed] [Google Scholar]
  38. Segaloff D. L., Ascoli M. The lutropin/choriogonadotropin receptor ... 4 years later. Endocr Rev. 1993 Jun;14(3):324–347. doi: 10.1210/edrv-14-3-324. [DOI] [PubMed] [Google Scholar]
  39. Segaloff D. L., Sprengel R., Nikolics K., Ascoli M. Structure of the lutropin/choriogonadotropin receptor. Recent Prog Horm Res. 1990;46:261–303. doi: 10.1016/b978-0-12-571146-3.50014-6. [DOI] [PubMed] [Google Scholar]
  40. Shaw J. H., Falkow S. Model for invasion of human tissue culture cells by Neisseria gonorrhoeae. Infect Immun. 1988 Jun;56(6):1625–1632. doi: 10.1128/iai.56.6.1625-1632.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Swanson J. Studies on gonococcus infection. XII. Colony color and opacity varienats of gonococci. Infect Immun. 1978 Jan;19(1):320–331. doi: 10.1128/iai.19.1.320-331.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sweet R. L., Blankfort-Doyle M., Robbie M. O., Schacter J. The occurrence of chlamydial and gonococcal salpingitis during the menstrual cycle. JAMA. 1986 Apr 18;255(15):2062–2064. [PubMed] [Google Scholar]
  43. Virji M., Makepeace K., Ferguson D. J., Watt S. M. Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic neisseriae. Mol Microbiol. 1996 Dec;22(5):941–950. doi: 10.1046/j.1365-2958.1996.01551.x. [DOI] [PubMed] [Google Scholar]
  44. Virji M., Watt S. M., Barker S., Makepeace K., Doyonnas R. The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitidis and Neisseria gonorrhoeae. Mol Microbiol. 1996 Dec;22(5):929–939. doi: 10.1046/j.1365-2958.1996.01548.x. [DOI] [PubMed] [Google Scholar]
  45. Weel J. F., Hopman C. T., van Putten J. P. In situ expression and localization of Neisseria gonorrhoeae opacity proteins in infected epithelial cells: apparent role of Opa proteins in cellular invasion. J Exp Med. 1991 Jun 1;173(6):1395–1405. doi: 10.1084/jem.173.6.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. van Putten J. P., Grassmé H. U., Robertson B. D., Schwan E. T. Function of lipopolysaccharide in the invasion of Neisseria gonorrhoeae into human mucosal cells. Prog Clin Biol Res. 1995;392:49–58. [PubMed] [Google Scholar]
  47. van Putten J. P., Paul S. M. Binding of syndecan-like cell surface proteoglycan receptors is required for Neisseria gonorrhoeae entry into human mucosal cells. EMBO J. 1995 May 15;14(10):2144–2154. doi: 10.1002/j.1460-2075.1995.tb07208.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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