#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Neisseria gonorrhoeae Infects the Heterogeneous Epithelia of the Human Cervix Using Distinct Mechanisms


Autoři: Qian Yu aff001;  Liang-Chun Wang aff001;  Sofia Di Benigno aff001;  Scott D. Gray-Owen aff003;  Daniel C. Stein aff001;  Wenxia Song aff001
Působiště autorů: Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, Maryland, United States of America aff001;  Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan aff002;  Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada aff003
Vyšlo v časopise: Neisseria gonorrhoeae Infects the Heterogeneous Epithelia of the Human Cervix Using Distinct Mechanisms. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008136
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008136

Souhrn

Sexually transmitted infections are a critical public health issue. However, the mechanisms underlying sexually transmitted infections in women and the link between the infection mechanism and the wide range of clinical outcomes remain elusive due to a lack of research models mimicking human infection in vivo. We established a human cervical tissue explant model to mimic local Neisseria gonorrhoeae (GC) infections. We found that GC preferentially colonize the ectocervix by activating integrin-β1, which inhibits epithelial shedding. GC selectively penetrate into the squamocolumnar junction (TZ) and endocervical epithelia by inducing β-catenin phosphorylation, which leads to E-cadherin junction disassembly. Epithelial cells in various cervical regions differentially express carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), the host receptor for GC opacity-associated proteins (OpaCEA). Relatively high levels were detected on the luminal membrane of ecto/endocervical epithelial cells but very low levels intracellularly in TZ epithelial cells. CEACAM-OpaCEA interaction increased ecto/endocervical colonization and reduced endocervical penetration by increasing integrin-β1 activation and inhibiting β-catenin phosphorylation respectively, through CEACAM downstream signaling. Thus, the intrinsic properties of cervical epithelial cells and phase-variation of bacterial surface molecules both play a role in controlling GC infection mechanisms and infectivity, preferential colonization or penetration, potentially leading to asymptomatic or symptomatic infection.

Klíčová slova:

Cell staining – Cytoplasmic staining – Epithelial cells – Epithelium – Molting – Scanning electron microscopy – Sexually transmitted diseases – Cervix


Zdroje

1. CDC. STD Facts (http://www.cdc.gov/std/gonorrhea/STDFact-gonorrhea-detailed.htm) Accessed Oct 5, 2017 2017. Available from: www.cdc.gov/std/gonorrhea/stdfact-gonorrhea.htm.

2. Unemo M, Del Rio C, Shafer WM. Antimicrobial Resistance Expressed by Neisseria gonorrhoeae: A Major Global Public Health Problem in the 21st Century. Microbiol Spectr. 2016;4(3). doi: 10.1128/microbiolspec.EI10-0009-2015 27337478; PubMed Central PMCID: PMC4920088.

3. Rice PA, Shafer WM, Ram S, Jerse AE. Neisseria gonorrhoeae: Drug Resistance, Mouse Models, and Vaccine Development. Annu Rev Microbiol. 2017;71:665–86. doi: 10.1146/annurev-micro-090816-093530 28886683.

4. Edwards JL, Apicella MA. The molecular mechanisms used by Neisseria gonorrhoeae to initiate infection differ between men and women. Clin Microbiol Rev. 2004;17(4):965–81, table of contents. doi: 10.1128/CMR.17.4.965-981.2004 15489357.

5. Edwards JL, Butler EK. The Pathobiology of Neisseria gonorrhoeae Lower Female Genital Tract Infection. Front Microbiol. 2011;2:102. doi: 10.3389/fmicb.2011.00102 21747805; PubMed Central PMCID: PMC3129011.

6. Bhattacharyya MN, Jephcott AE, Morton RS. Diagnosis of gonorrhoea in women: comparison of sampling sites. Br Med J. 1973;2(5869):748–50. doi: 10.1136/bmj.2.5869.748 4736958; PubMed Central PMCID: PMC1589763.

7. Harkness AH. The pathology of gonorrhoea. Br J Vener Dis. 1948;24(4):137–47. 18099876

8. Kenemans P, Davina J, de Hann RW, Hafez ESE. The Cervix. In: Kenemans ESEHaP, editor. Atlas of Human Reproduction by Scanning Electron Microscopy. Hingham, MA: MTP PRess; 1982. p. 45–54.

9. Kurita T. Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation. 2011;82(3):117–26. Epub 2011/05/27. doi: 10.1016/j.diff.2011.04.008 21612855; PubMed Central PMCID: PMC3178098.

10. Segal E, Billyard E, So M, Storzbach S, Meyer TF. Role of chromosomal rearrangement in Neisseria gonorrhoeae pilus phase variation. Cell. 1985;40:293–302. doi: 10.1016/0092-8674(85)90143-6 2857113

11. Stern A, Brown M, Nickel P, Meyer TF. Opacity genes of Neisseria gonorrhoeae: control of phase and antigenic variation. Cell. 1986;47:61–71. doi: 10.1016/0092-8674(86)90366-1 3093085

12. Swanson J. Studies on gonococcus infection. IV. Pili: their role in attachment of gonococci to tissue culture cells. J Exp Med. 1973;137(3):571–89. doi: 10.1084/jem.137.3.571 4631989

13. van Putten JP, Paul SM. Binding of syndecan-like cell surface proteoglycan receptors is required for Neisseria gonorrhoeae entry into human mucosal cells. EMBO J. 1995;14(10):2144–54. 7774572

14. Virji M, Makepeace K, Ferguson DJ, Watt SM. Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic neisseriae. Mol Microbiol. 1996;22(5):941–50. Epub 1996/12/01. doi: 10.1046/j.1365-2958.1996.01551.x 8971715.

15. Gray-Owen SD, Dehio C, Haude A, Grunert F, Meyer TF. CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes. EMBO J. 1997;16(12):3435–45. doi: 10.1093/emboj/16.12.3435 9218786; PubMed Central PMCID: PMC1169969.

16. Edwards JL, Brown EJ, Uk-Nham S, Cannon JG, Blake MS, Apicella MA. A co-operative interaction between Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary cervical epithelial cells. Cell Microbiol. 2002;4(9):571–84. doi: 10.1046/j.1462-5822.2002.t01-1-00215.x 12390350.

17. Edwards JL, Apicella MA. I-domain-containing integrins serve as pilus receptors for Neisseria gonorrhoeae adherence to human epithelial cells. Cell Microbiol. 2005;7(8):1197–211. doi: 10.1111/j.1462-5822.2005.00547.x 16008586.

18. Hauck CR, Meyer TF. 'Small' talk: Opa proteins as mediators of Neisseria-host-cell communication. Curr Opin Microbiol. 2003;6(1):43–9. doi: 10.1016/s1369-5274(03)00004-3 12615218.

19. Billker O, Popp A, Gray-Owen SD, Meyer TF. The structural basis of CEACAM-receptor targeting by neisserial Opa proteins. Trends Microbiol. 2000;8(6):258–60. doi: 10.1016/s0966-842x(00)01771-6 10838580.

20. Chen T, Belland RJ, Wilson J, Swanson J. Adherence of pilus- Opa+ gonococci to epithelial cells in vitro involves heparan sulfate. J Exp Med. 1995;182(2):511–7. doi: 10.1084/jem.182.2.511 7629509; PubMed Central PMCID: PMC2192128.

21. Chen T, Grunert F, Medina-Marino A, Gotschlich EC. Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. J Exp Med. 1997;185(9):1557–64. doi: 10.1084/jem.185.9.1557 9151893; PubMed Central PMCID: PMC2196295.

22. Islam EA, Anipindi VC, Francis I, Shaik-Dasthagirisaheb Y, Xu S, Leung N, et al. Specific Binding to Differentially Expressed Human Carcinoembryonic Antigen-Related Cell Adhesion Molecules Determines the Outcome of Neisseria gonorrhoeae Infections along the Female Reproductive Tract. Infect Immun. 2018;86(8). Epub 2018/05/16. doi: 10.1128/iai.00092-18 29760215; PubMed Central PMCID: PMC6056862.

23. Schmitter T, Pils S, Weibel S, Agerer F, Peterson L, Buntru A, et al. Opa proteins of pathogenic neisseriae initiate Src kinase-dependent or lipid raft-mediated uptake via distinct human carcinoembryonic antigen-related cell adhesion molecule isoforms. Infect Immun. 2007;75(8):4116–26. doi: 10.1128/IAI.01835-06 17517873; PubMed Central PMCID: PMC1952016.

24. Boulton IC, Gray-Owen SD. Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nat Immunol. 2002;3(3):229–36. doi: 10.1038/ni769 11850628.

25. Nagaishi T, Pao L, Lin SH, Iijima H, Kaser A, Qiao SW, et al. SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity. 2006;25(5):769–81. Epub 2006/11/04. doi: 10.1016/j.immuni.2006.08.026 17081782.

26. Lee HS, Ostrowski MA, Gray-Owen SD. CEACAM1 dynamics during Neisseria gonorrhoeae suppression of CD4+ T lymphocyte activation. J Immunol. 2008;180(10):6827–35. doi: 10.4049/jimmunol.180.10.6827 18453603.

27. Muenzner P, Rohde M, Kneitz S, Hauck CR. CEACAM engagement by human pathogens enhances cell adhesion and counteracts bacteria-induced detachment of epithelial cells. J Cell Biol. 2005;170:825–36. doi: 10.1083/jcb.200412151 16115956

28. Muenzner P, Bachmann V, Zimmermann W, Hentschel J, Hauck CR. Human-restricted bacterial pathogens block shedding of epithelial cells by stimulating integrin activation. Science. 2010;329(5996):1197–201. doi: 10.1126/science.1190892 20813953

29. Wang J, Gray-Owen SD, Knorre A, Meyer TF, Dehio C. Opa binding to cellular CD66 receptors mediates the transcellular traversal of Neisseria gonorrhoeae across polarized T84 epithelial cell monolayers. Mol Microbiol. 1998;30(3):657–71. doi: 10.1046/j.1365-2958.1998.01102.x 9822830

30. Wang LC, Yu Q, Edwards V, Lin B, Qiu J, Turner JR, et al. Neisseria gonorrhoeae infects the human endocervix by activating non-muscle myosin II-mediated epithelial exfoliation. PLoS Pathog. 2017;13(4):e1006269. Epub 2017/04/13. doi: 10.1371/journal.ppat.1006269 28406994; PubMed Central PMCID: PMC5391109.

31. Schurch W, McDowell EM, Trump BF. Long-term organ culture of human uterine endocervix. Cancer Res. 1978;38(11 Pt 1):3723–33. Epub 1978/11/01. 698932.

32. Bos MP, Kuroki M, Krop-Watorek A, Hogan D, Belland RJ. CD66 receptor specificity exhibited by neisserial Opa variants is controlled by protein determinants in CD66 N-domains. Proc Natl Acad Sci U S A. 1998;95(16):9584–9. Epub 1998/08/05. doi: 10.1073/pnas.95.16.9584 9689124; PubMed Central PMCID: PMC21382.

33. LeVan A, Zimmerman LI, Mahle AC, Swanson KV, DeShong P, Park J, et al. Construction and characterization of a derivative of Neisseria gonorrhoeae strain MS11 devoid of all opa genes. J Bacteriol. 2012;194(23):6468–78. Epub 2012/09/25. doi: 10.1128/JB.00969-12 JB.00969-12 [pii]. 23002223; PubMed Central PMCID: PMC3497525.

34. Stein DC, LeVan A, Hardy B, Wang LC, Zimmerman L, Song W. Expression of Opacity Proteins Interferes with the Transmigration of Neisseria gonorrhoeae across Polarized Epithelial Cells. PLoS One. 2015;10(8):e0134342. doi: 10.1371/journal.pone.0134342 26244560; PubMed Central PMCID: PMC4526573.

35. Villullas S, Hill DJ, Sessions RB, Rea J, Virji M. Mutational analysis of human CEACAM1: the potential of receptor polymorphism in increasing host susceptibility to bacterial infection. Cell Microbiol. 2007;9(2):329–46. Epub 2006/08/31. doi: 10.1111/j.1462-5822.2006.00789.x 16953805; PubMed Central PMCID: PMC1859983.

36. Bamberger A-M, Briese J, Götze J, Erdmann I, Schulte HM, Wagener C, et al. Stimulation of CEACAM1 expression by 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophore A23187 in endometrial carcinoma cells. Carcinogenesis. 2006;27(3):483–90. doi: 10.1093/carcin/bgi275 16332726

37. Gray-Owen SD, Blumberg RS. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol. 2006;6(6):433–46. Epub 2006/05/26. doi: 10.1038/nri1864 16724098.

38. Huber M, Izzi L, Grondin P, Houde C, Kunath T, Veillette A, et al. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J Biol Chem. 1999;274(1):335–44. Epub 1998/12/29. doi: 10.1074/jbc.274.1.335 9867848.

39. Capaldo CT, Farkas AE, Nusrat A. Epithelial adhesive junctions. F1000Prime Rep. 2014;6:1. doi: 10.12703/P6-1 24592313; PubMed Central PMCID: PMC3883420.

40. Tchoupa AK, Schuhmacher T, Hauck CR. Signaling by epithelial members of the CEACAM family—mucosal docking sites for pathogenic bacteria. Cell Commun Signal. 2014;12:27. doi: 10.1186/1478-811X-12-27 24735478; PubMed Central PMCID: PMC4057559.

41. Simoneau M, Coulombe G, Vandal G, Vézina A, Rivard N. SHP-1 inhibits β-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. Cell Signal. 2011;23(1):269–79. Epub 2010/09/16. doi: 10.1016/j.cellsig.2010.09.011 20840866.

42. Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012;31(12):2714–36. Epub 2012/05/22. doi: 10.1038/emboj.2012.150 22617422; PubMed Central PMCID: PMC3380220.

43. Hendrickson MR, Kempson RL. Normal histology of the uterus and fallopian tubes. In: Sternberg SS, editor. Histology for Pathologists, 2nd edn. Philadelphia: Lippincott Williams and Wilkins; 1997. p. pp 879–927.

44. Wachter J, Hill S. Positive Selection Pressure Drives Variation on the Surface-Exposed Variable Proteins of the Pathogenic Neisseria. PLoS One. 2016;11(8).

45. Sintsova A, Wong H, MacDonald KS, Kaul R, Virji M, Gray-Owen SD. Selection for a CEACAM receptor-specific binding phenotype during Neisseria gonorrhoeae infection of the human genital tract. Infect Immun. 2015;83(4):1372–83. doi: 10.1128/IAI.03123-14 25605771; PubMed Central PMCID: PMC4363431.

46. Muenzner P, Bachmann V, Kuespert K, Hauck CR. The CEACAM1 transmembrane domain, but not the cytoplasmic domain, directs internalization of human pathogens via membrane microdomains. Cell Microbiol. 2008;10(5):1074–92. doi: 10.1111/j.1462-5822.2007.01106.x 18081725.

47. Iwamoto DV, Calderwood DA. Regulation of integrin-mediated adhesions. Curr Opin Cell Biol. 2015;36:41–7. doi: 10.1016/j.ceb.2015.06.009 26189062; PubMed Central PMCID: PMC4639423.

48. Jerse AE. Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Infection and Immunity. 1999;67(11):5699–708. ISI:000083343000021. 10531218

49. Kupsch EM, Knepper B, Kuroki T, Heuer I, Meyer TF. Variable opacity (Opa) outer membrane proteins account for the cell tropisms displayed by Neisseria gonorrhoeae for human leukocytes and epithelial cells. EMBO J. 1993;12(2):641–50. 8440254; PubMed Central PMCID: PMC413248.

50. Melly MA, Gregg CR, McGee ZA. Studies of toxicity of Neisseria gonorrhoeae for human fallopian tube mucosa. J Infect Dis. 1981;143(3):423–31. doi: 10.1093/infdis/143.3.423 6785364.

51. Virji M, Kayhty H, Ferguson DJ, Alexandrescu C, Heckels JE, Moxon ER. The role of pili in the interactions of pathogenic Neisseria with cultured human endothelial cells. Mol Microbiol. 1991;5(8):1831–41. doi: 10.1111/j.1365-2958.1991.tb00807.x 1722554

52. Schmidt KA, Deal CD, Kwan M, Thattassery E, Schneider H. Neisseria gonorrhoeae MS11mkC opacity protein expression in vitro and during human volunteer infectivity studies. Sex Transm Dis. 2000;27(5):278–83. doi: 10.1097/00007435-200005000-00008 10821601.

53. Sadarangani M, Pollard AJ, Gray-Owen SD. Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria. FEMS Microbiol Rev. 2010;35:498–514. Epub 2011/01/06. doi: 10.1111/j.1574-6976.2010.00260.x 21204865.

54. Evans BA. Ultrastructural study of cervical gonorrhea. J Infect Dis. 1977;136(2):248–55. doi: 10.1093/infdis/136.2.248 408425.

55. White LA, Kellogg DS. An improved fermentation medium for Neisseria gonorrhoeae and other Neisseria. Health Lab Sci. 1965;2(4):238–41. 4953822.

56. Wang LC, Yu Q, Stein DC, Song W. Immunofluorescence Analysis of Human Endocervical Tissue Explants Infected with Neisseria gonorrhoeae. Bio Protoc. 2018;8(3). doi: 10.21769/BioProtoc.2720 29780854; PubMed Central PMCID: PMC5959038.

57. Edwards VL, Wang LC, Dawson V, Stein DC, Song W. Neisseria gonorrhoeae breaches the apical junction of polarized epithelial cells for transmigration by activating EGFR. Cell Microbiol. 2013;15(6):1042–57. doi: 10.1111/cmi.12099 23279089

Štítky
Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens


2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Halitóza
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#