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Cell Stress and Chaperones

, Volume 15, Issue 5, pp 467–473 | Cite as

Immunopathogenic consequences of Chlamydia trachomatis 60 kDa heat shock protein expression in the female reproductive tract

  • Iara Moreno Linhares
  • Steven S. Witkin
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Abstract

Chlamydia trachomatis is an obligate intracellular bacterium that infects chiefly urogenital and ocular epithelial cells. In some infected women the microorganism migrates to the upper reproductive tract resulting in a chronic, but asymptomatic, infection. The immune response to this infection, production of interferon-γ and pro-inflammatory cytokines, results in interruption of chlamydial intracellular replication. However, the Chlamydia remains viable and enters into a persistent state. In this form, most chlamydial genes are inactive. An exception is the gene coding for the 60 kDa heat shock protein (hsp60), which is synthesized in increased amounts and is released into the extracellular milieu. The chronic release of chlamydial hsp60 induces a local pro-inflammatory immune response in fallopian tube epithelia and results in scar formation and tubal occlusion. In addition, long-term exposure of the maternal immune system to the chlamydial hsp60 eventually results in the release of tolerance and generation of an immune response that recognizes regions of the chlamydial hsp60 that are also present in the human hsp60. Production of cross-reacting antibodies and cell-mediated immunity to the human hsp60 is detrimental to subsequent pregnancy outcome and may also possibly increase susceptibility to atherosclerosis, autoimmune disorders, or malignancies.

Keywords

Chlamydia trachomatis 60 kDa heat shock protein Persistence Autoimmunity Infertility 

References

  1. Beatty WL, Byrne GI, Morrison RP (1993a) Morphologic and antigenic characterization of interferon γ-mediated persistent Chlamydia trachomatis infection in vitro. Proc Natl Acad Sci USA 90:3998–4002CrossRefPubMedGoogle Scholar
  2. Beatty WL, Byrne GI, Morrison RP (1993b) Repeated and persistent infection with Chlamydia and the development of chronic inflammation and disease. Trends Microbiol 2:94–98CrossRefGoogle Scholar
  3. Beatty WL, Morrison RP, Byrne GI (1994) Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiol Rev 58:686–699PubMedGoogle Scholar
  4. Belhia F, Gremlich S, Damnon F, Hohlfeld P, Witkin SS, Gerber S (2010) Anti-60 kDa heat shock protein antibodies in fetal serum: marker of unexplained small for gestational age fetuses. Gynecol Obstet Invest, In pressGoogle Scholar
  5. Bensuade O, Morange M (1981) Spontaneous high expression of heat shock proteins in mouse embryonal cells and ectoderm from day 8 mouse embryo. EMBO J 2:173–177Google Scholar
  6. Brudzynski K (1993) Insulitis-caused redistribution of heat-shock protein HSP60 inside beta-cells correlates with induction of HSP60 autoantibodies. Diabetes 42:908–913CrossRefPubMedGoogle Scholar
  7. Brunham RC, Rekart ML (2009) Considerations on Chlamydia trachomatis disease expression. FEMS Immunol Med Microbiol 55:162–166CrossRefPubMedGoogle Scholar
  8. Caldwell HD, Wood H, Crane D, Bailey R, Jones RB, Mabey D, Maclean I, Mohammed Z, Peeling R, Roshick C, Schachter J, Solomon AW, Stamm WE, Suchland RJ, Taylor L, West SK, Quinn TC, Belland RJ, McClarty G (2003) Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates. J Clin Invest 111:1757–1769PubMedGoogle Scholar
  9. Campanella C, Gammazza AM, Mularoni L, Cappello F, Zummo G, Di Felice V (2008) A comparative analysis of the products of GROEL-1 gene from Chlamydia trachomatis serovar D and the HSP60 var1 transcript from Homo sapiens suggests a possible autoimmune response. Int J Immunogenet 36:73–78CrossRefGoogle Scholar
  10. Campbell LA, Patton DL, Moore DE, Cappuccio AL, Mueller BA, Wang SP (1993) Detection of Chlamydia trachomatis deoxyribonucleic acid in women with tubal infertility. Fertil Steril 59:45–50PubMedGoogle Scholar
  11. Cappello F, de Macario EC, Di Felice V, Zummo G, Macario AJL (2009) Chlamydia trachomatis infection and anti-hsp60 immunity: the two sides of the coin. PloS Pathog 5(8):e1000552. doi: 10.1371/journal.ppat.1000552 CrossRefPubMedGoogle Scholar
  12. Cates W Jr, Joesef MR, Goldman MB (1993) Atypical pelvic inflammatory disease: can we identify clinical predictors? Am J Obstet Gynecol 169:341–346PubMedGoogle Scholar
  13. Dabekausen YA, Evers JL, Land JA, Stals FS (1994) Chlamydia trachomatis antibody testing is more accurate than hysterosalpingography in predicting tubal factor infertility. Fertil Steril 61:833–837PubMedGoogle Scholar
  14. Dean D, Powell VC (2001) Persistent Chlamydia trachomatis infections resist apoptotic stimuli. Infect Immun 69:2442–2447CrossRefPubMedGoogle Scholar
  15. Dean D, Suchland RJ, Stamm WE (2000) Evidence for long-term cervical persistence of Chlamydia trachomatis by omp1 genotyping. J Infect Dis 182:909–918CrossRefPubMedGoogle Scholar
  16. Di Felice V, David S, Cappello F, Farina F, Zummo G (2005) Is chlamydial heat shock protein 60 a risk factor for oncogenesis? Cell Mol Life Sci 62:4–9CrossRefPubMedGoogle Scholar
  17. Domeika M, Domeika K, Paavonen J, Mardh PA, Witkin SS (1998) Humoral immune response to conserved epitopes of Chlamydia trachomatis and human 60-kDa heat- shock protein in women with pelvic inflammatory disease. J Infect Dis 177:714–719CrossRefPubMedGoogle Scholar
  18. Equils O, Lu D, Gatter M, Witkin SS, Bertolotto C, Arditi M, McGregor JA, Simmons CF, Hobel CJ (2006) Chlamydia heat shock protein 60 induces trophoblast apoptosis through TLR4. J Immunol 177:1257–1263PubMedGoogle Scholar
  19. Forhan SE, Gottlieb SL, Sternberg MR, Xu F, Datta SD, McQuillan GM, Berman SM, Markowitz LE (2009) Prevalence of sexually transmitted infections among female adolescents aged 14 to 19 in the United States. Pedatrics 124:1505–1512CrossRefGoogle Scholar
  20. Gerard HC, Branigan PJ, Balsara GR, Heath C, Minassian SS, Hudson AP (1998) Viability of Chlamydia trachomatis in fallopian tubes of patients with ectopic pregnancy. Fertil Steril 70:945–948CrossRefPubMedGoogle Scholar
  21. Gerard HC, Whittum-Hudson JA, Schumacher HR, Hudson AP (2004) Differential expression of three Chlamydia trachomatis hsp60-encoding genes in active vs. persistent infections. Microb Pathog 36:35–39CrossRefPubMedGoogle Scholar
  22. Goyal K, Qamra R, Mande SC (2006) Multiple gene duplication and rapid evolution in the GroEL gene: functional implications. J Mol Evol 63:781–787CrossRefPubMedGoogle Scholar
  23. Greene W, Xiao Y, Huang Y, McClarty G, Zhng G (2004) Chlamydia – infected cells continue to undergo mitosis and resist induction of apoptosis. Infect Immun 72:451–460CrossRefPubMedGoogle Scholar
  24. Heybourne K, Fu YX, Nelson A, Farr A, O’Brien R, Born W (1994) Recognition of trophoblast by γδ T cells. J Immunol 153:2918–2926Google Scholar
  25. Holland SM, Hudson AP, Bobo L, Whittum-Hudson JA, Viscidi RP, Quinn TC, Taylor HR (1992) Demonstration of chlamydial RNA and DNA during a culture-negative state. Infect Immun 60:2040–2047PubMedGoogle Scholar
  26. Holtmann H, Shemer-Avni Y, Wessel K, Sarov I, Wallach D (1990) Inhibition of growth of Chlamydia trachomatis by tumor necrosis factor is accompanied by increased prostaglandin synthesis. Infect Immun 58:3168–3172PubMedGoogle Scholar
  27. Jakus S, Neuer A, Dieterle S, Bongiovanni AM, Witkin SS (2008) Antibody to the Chlamydia trachomatis 60 kDa heat shock protein in follicular fluid and in vitro fertilization outcome. Am J Reprod Immunol 59:85–89PubMedGoogle Scholar
  28. Jendro MC, Deutsch T, Korber B, Kohler L, Kuipers JG, Krausse-Opatz B, Westermann J, Raum E, Ziedler H (2000) Infection of human monocyte-derived macrophages with Chlamydia trachomatis induces apoptosis of T cells: a potential mechanism for persistent infection. Infect Immun 68:6704–6711CrossRefPubMedGoogle Scholar
  29. Jendro MC, Fingerle F, Deutsch T, Liese A, Kohler L, Kuipers JG, Raum E, Martin M, Zeidler H (2004) Chlamydia trachomatis-infected macrophages induce apoptosis of activated T cells by secretion of tumor necrosis factor-alpha in vitro. Med Microbiol Immunol 193:45–52CrossRefPubMedGoogle Scholar
  30. Karunakaran KP, Noguchi Y, Read TD, Cherkasov A, Kwee J, Shen C, Nelson CC, Brunham RC (2003) Molecular analysis of the multiple GroEL proteins of Chlamydiae. J Bacteriol 185:1958–1966CrossRefPubMedGoogle Scholar
  31. Kinnunen A, Molander P, Laurila A, Rantala I, Morrison R, Lehtinen M, Karttunen R, Tiitinen A, Paavonen J, Surcel HM (2000) Chlamydia trachomatis reactive T lymphocytes from upper genital tract tissue specimens. Hum Reprod 15:1484–1489CrossRefPubMedGoogle Scholar
  32. Kinnunen A, Surcel HM, Lehtinen M, Karhukorpi J, Tiitinen A, Halttunen M, Bloigu A, Morrison RP, Karttunen R, Paavonen J (2002) HLA DQ alleles and interleukin-10 polymorphism associated with Chlamydia trachomatis-associated tubal factor infertility: a case-control study. Hum Reprod 17:2073–2078CrossRefPubMedGoogle Scholar
  33. Kligman I, Jeremias J, Rosenwaks Z, Witkin SS (1998) Cell-mediated immunity to human and Escherichia coli 60-kDa heat shock protein in women: Association with a history of spontaneous abortion and endometriosis. Am J Reprod Immunol 40:32–36PubMedGoogle Scholar
  34. Kramer MJ, Gordon FB (1971) Ultrastructural analysis of the effects of penicillin and chlortetracycline on the development of a genital tract Chlamydia. Infect Immun 3:333–341PubMedGoogle Scholar
  35. Lichtenwalner AB, Patton DL, Van Voorhis WC, Cosgrove Sweeney YT, Kuo CC (2004) Heat shock protein 60 is the major antigen which stimulates delayed-type hypersensitivity reaction in the Macaque model of Chlamydia trachomatis salpingitis. Infect Immun 72:1159–1161CrossRefPubMedGoogle Scholar
  36. Mabey D, Peeling RW (2002) Lymphogranula venereum. Sex Trans Infect 78:90–92CrossRefGoogle Scholar
  37. Mascellino MT, Ciardi MR, Oliva A, Cecinato F, Hassemer MP, Borgese L (2008) Chlamydia trachomatis detection in a population of asymptomatic and symptomatic women: correlation with the presence of serological markers for this infection. New Microbiol 31:249–256PubMedGoogle Scholar
  38. Mincheva-Nilsson L, Baranov Y, Yeung MM, Hammarstrom S, Hammarstrom ML (1994) Immunomorphologic studies of human decidua-associated lymphoid cells in normal early pregnancy. J Immunol 152:2020–2032PubMedGoogle Scholar
  39. Molano M, Meijer CJ, Weiderpass E, Arslan A, Posso H, Franceshi S, Ronderos M, Munoz N, van den Drule AJ (2005) The natural course of Chlamydia trachomatis infection in asymptomatic Colombian women: 1 5-year follow-up study. J Infect Dis 191:907–916CrossRefPubMedGoogle Scholar
  40. Morrison RP (1991) Chlamydial hsp60 and the immunopathogenesis of chlamydial disease. Seminars in Immunol 3:25–33Google Scholar
  41. Neuer A, Ruck P, Marzusch K, Dietl J, Kaiserling E, Horny HP, Witkin SS (1996) Human heat shock proteins in first trimester human decidua. Infect Dis Obstet Gynecol 4:188–189Google Scholar
  42. Neuer A, Lam KN, Tiller FW, Kiesel L, Witkin SS (1997) Humoral immune response to membrane components of Chlamydia trachomatis and expression of the human 60 kDa heat shock protein in follicular fluid of in-vitru fertilization patients. Hum Reprod 12:925–929CrossRefPubMedGoogle Scholar
  43. Neuer A, Mele C, Liu HC, Rosenwaks Z, Witkin SS (1998) Monoclonal antibodies to mammalian heat shock proteins impair mouse embryo development in vitro. Hum Reprod 13:987–990CrossRefPubMedGoogle Scholar
  44. Ondondo BO, Brunham RC, Harrison WG, Kinyari T, Sheth PM, Mugo NR, Cohen CR (2009) Frequency and magnitude of Chlamydia trachomatis elementary body- and heat shock protein 60-stimulated interferon γ responses in peripheral blood mononuclear cells and endometrial biopsy samples from women with high exposure to infection. J Infect Dis 199:1771–1779CrossRefPubMedGoogle Scholar
  45. Patton DL, Askienazy-Elbar M, Henry-Suchet J, Campbell LA, Cappuccio A, Tannous W, Wang SP, Kuo CC (1994a) Detection of Chlamydia trachomatis in fallopian tube tissue in women with postinfectious tubal infertility. Am J Obstet Gynecol 171:95–101PubMedGoogle Scholar
  46. Patton DL, Sweeney YT, Kuo CC (1994b) Demonstration of a delayed hypersensitivity in Chlamydia trachomatis salpingitis in monkeys: a pathogenic mechanism of tubal damage. J Infect Dis 169:680–683PubMedGoogle Scholar
  47. Peeling RW, Brunham RC (1996) Chlamydiae as pathogens: new species and new issues. Emerg Infect Dis 2:307–319CrossRefPubMedGoogle Scholar
  48. Peeling RW, Bailey RL, Conway DJ, Holland MJ, Campbell AE, Jallow O, Whittle HC, Mabey CW (1998) Antibody response to the 60-kDa chlamydial heat-shock protein is associated with scarring trachoma. J Infect Dis 177:256–259CrossRefPubMedGoogle Scholar
  49. Perschinka H, Mayr M, Millonig G, Mayeri C, van der Zee R, Morrison SG, Morrison RP, Xu Q, Wick G (2003) Cross-reactive B cell epitopes on microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 23:1060–1065CrossRefPubMedGoogle Scholar
  50. Shin BK, Wang H, Yim AM, Le Naour F, Brichory F, Jang JH, Zhao R, Puravs E, Tra J, Michael CW, Misek DE, Hanash SM (2003) Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J Biol Chem 278:7607–7616CrossRefPubMedGoogle Scholar
  51. Skilton RJ, Cutcliffen LT, Barlow D, Wang Y, Salim O, Lambden PR, Clarke IN (2009) Penicillin induced persistence in Chlamydia trachomatis: high quality time lapse video analysis of the developmental cycle. PLoS ONE 4:e7723CrossRefPubMedGoogle Scholar
  52. Sziller I, Witkin SS, Ziegert M, Csapo Z, Ujhazy A, Papp Z (1998) Serological responses of patients with ectopic pregnancy to epitopes of the Chlamydia trachomatis 60 kDa heat shock protein. Hum Reprod 13:1088–1093CrossRefPubMedGoogle Scholar
  53. Sziller I, Babula O, Ujhazy A, Nagy B, Hupuczi P, Papp Z, Linhares IM, Ledger WJ, Witkin SS (2007) Chlamydia trachomatis infection, fallopian tube damage and a mannose-binding lectin codon 54 gene polymorphism. Hum Reprod 22:1861–1865CrossRefPubMedGoogle Scholar
  54. Sziller I, Fedorcsak P, Csapo Z, Szirmal K, Linhares IM, Papp Z, Witkin SS (2008) Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60-kDa heat shock protein is associated with decreased spontaneous fertility rate in ectopic pregnant women treated by salpingectomy. Am J Reprod Immunol 59:99–104PubMedGoogle Scholar
  55. Tiitinen A, Surcel HM, Halttunen M, Birkelund S, Bloigu A, Christiansen G, Koskela P, Morrison SG, Morrison RP, Paavonen J (2006) Chlamydia trachomatis and chlamydial heat shock protein 60-specific antibody and cell-mediated responses predict tubal factor infertility. Hum Reprod 21:1533–1538CrossRefPubMedGoogle Scholar
  56. Toth M, Patton DL, Campbell LA, Carretta EJ, Mouradian J, Toth A, Shevchuk M, Baergen R, Ledger W (2000) Detection of chlamydial antigenic material in ovarian, prostatic, ectopic pregnancy and semen samples of culture-negative subjects. Am J Reprod Immunol 43:218–222CrossRefPubMedGoogle Scholar
  57. Ward ME (1995) The immunobiology and immunopathology of chlamydial infections. APMIS 103:769–796CrossRefPubMedGoogle Scholar
  58. Witkin SS, Jeremias J, Toth M, Ledger WJ (1993) Cell-mediated immune response to the recombinant 57-kDa heat-shock protein of Chlamydia trachomatis in women with salpingitis. J Infect Dis 167:1379–1383PubMedGoogle Scholar
  59. Witkin SS, Jeremias J, Toth M, Ledger WJ (1994a) Proliferative response to conserved epitopes of the Chlamydia trachomatis and human 60-kilodalton heat-shock proteins by lymphocytes from women with salpingitis. Am J Obstet Gynecol 171:455–460PubMedGoogle Scholar
  60. Witkin SS, Sultan KM, Neal GS, Jeremias J, Grifo JA, Rosenwaks Z (1994b) Unsuspected Chlamydia trachomatis infection and in vitro fertilization outcome. Am J Obstet Gynecol 171:1208–1214PubMedGoogle Scholar
  61. Witkin SS, Jeremias J, Neuer A, David SS, Willner E, Witkin KL (1996) Immune recognition of the 60-kD heat shock protein: implications for subsequent fertility. Infect Dis Obstet Gynecol 4:152–158CrossRefPubMedGoogle Scholar
  62. Witkin SS, Askienazy-Elbhar M, Henry-Suchet J, Belaisch-Allart J, Tort-Grunbach J, Sarjdine K (1998) Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60 kDa heat shock protein (hsp60) in infertile couples and its relationship to antibodies to C. trachomatis surface antigens and the Escherichia coli and human hsp60. Hum Reprod 13:1175–1179CrossRefPubMedGoogle Scholar
  63. Workowski KA, Berman SM (2006) Sexually transmitted diseases treatment guidelines. MMWR Recomm Rep 55:1–94PubMedGoogle Scholar
  64. Wyrick PB (2000) Intracellular survival by Chlamydia. Cell Microbiol 2:275–282CrossRefPubMedGoogle Scholar
  65. Ziegert M, Witkin SS, Sziller I, Alexander H, Brylla E, Hartig W (1999) Heat shock proteins and heat shock protein-antibody complexes in placental tissues. Infect Dis Obstet Gynecol 7:180–185CrossRefPubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2010

Authors and Affiliations

  1. 1.Division of Immunology and Infectious Diseases, Department of Obstetrics and GynecologyWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Department of GynecologyUniversity of Sao Paulo Medical School and Hospital das ClinicasSao PauloBrazil

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