Persistent Chlamydia Female Genital Tractdownloads.hindawi.com/journals/idog/1999/264824.pdfG, CherneskyMA,et al (eds). Monvillargeney, France, 1994, p 599-610. 2. Henry-Suchet J,

Infectious Diseases in Obstetrics and Gynecology 7:31-34 (1999)(C) 1999 Wiley-Liss, Inc.

Persistent "Silent" Chlamydia trachomatis FemaleGenital Tract Infections

M. Askienazy-Elbhar1. and J. Henry-Suchet21Laboratoire de Bio/ogie Mgdica/e Magenta, Paris, France

eC.H. Jean Rostand, Svres, France

KEY WORDS

Chlamydia trachomatis; infection; heat shock proteins

hronic chlamydial infections have been docu-mented in numerous works 1,z as silently

evolving diseases. Evidence of resistance to antibi-otic therapy, as demonstrated by positive cultureslong after treatment in infertile women,3,4 as wellas positive chlamydial antigens or nucleic acids inculture-negative pelvic samples of infertilewomens and the discovery of chlamydial RNA andinflammatory cytokines transcripts in tubes6 or

joints, 7 have led investigators to consider persis-tence of the infectious material responsible for theacquisition of chronicity. So far, animal models innumerous works have proved the persistence ofviable chlamydiae in altered cell cultures. Manyauthors have also associated serious sequelae of un-suspected silent infections with the genetically re-

stricted host response to the heat shock proteins(Hsps) secreted by bacteria, especially Hsp60 andHspT0, which correspond to the chlamydial Gro-E1and DNA-K genes,9-1z suggesting that repeated or

prolonged exposure to the Hsp antigens is respon-sible for the strong host response against these bac-terial Hsps and against self-Hsps homologous to

the bacterial ones. The consequence of the allo-immunity to chlamydial antigens and Hsps, and ofthe autoimmunity to self-Hsps, is persistent in-flammation, scarring, fibrosis, and necrosis. Theclinical long-term female diseases documented are

ectopic pregnancy with altered ciliary tubal func-tion, tubal infertility with obstructed tubes, andearly embryo rejection with immune interfer-

ence 14,1s in women undergoing in vitro fertilizationfor tubal factor infertility. A normal chlamydialgrowth can give viable chlamydiae recovered fromsick tissues of obstructed tubes without any previ-ous notice of pelvic inflammatory disease (PID);conversely, persistent chlamydiae can produceovert infections. But, culture is almost impossibleunless multiple serial passages 16 are performed inmost chronic cases. It is not known whetherchronic chlamydial disease is a consequence of an

evolving silent (asymptomatic) infection, a naturalinfection, or a thoroughly treated and eradicatedinfection.The clinical assumption of persistent chlamydial

infection in the genital tract has been reached bythe observation of functional disease associatedwith a previous infection, documented by positivechlamydial antibodies. The infectious etiology oftubal obstruction has been assessed by several au-

thors, most often by chlamydial antibody testing, a7

However, it has never been clear whether anti-

chlamydial immunoglobulin (Ig) G is only a sero-

logic scar in the absence of specific IgA or IgM, nor

whether untreated cervical chlamydial infectionwould ascend to the upper genital tract or self-resolve, nor which infection would persist even af-ter treatment with and evolve with the host tissue

division.The implication of Chlamydia trachomatis with

mucopurulent cervicitis and plasma cell endome-tritis was found of 64% of asymptomatic women in

*Correspondence to: M. Askienazy-Elbhar, Laboratoire de Biologie M6dicale Magenta, 41 Boulevard de Magenta, 75010Paris, France.

SILENT CHLAMYDIA TRACHOMATIS INFECTIONS ASKIENAZY-ELBHAR AND HENRY-SUCHET

a recent work. 18 Sexually transmitted pathogenslike C. trachomatis and Neisseria gonorrhoeae play a

starter role in the infection by ascending the cervix,followed by anaerobic and bacterial vaginosis-associated bacteria. Pelvic inflammatory diseaseand C. trachomatis are strongly associated. In a C.trachomatis-PID model, 19 pro-inflammatory cyto-kines were induced in the cervix 20 hours afterinfection. Recurrent infections increase the risk forPID, and prior PID increases the risk for infertil-

ity,z similar to the progressive scarring caused bychronic trachoma. Susceptibility for PID is geneti-cally restricted by the human leukocyte antigenclass-I antigens,z,zz A significantly higher preva-lence of anti-C Hsp60 antibodies has been found inpatients with occluded tubes (90%) than in patientsfrom a sexually transmitted disease clinic infectedwith C. trachomatis. 9 C Hsp60 induces chronic T-cell immunopathogenesis and produces autoim-mune cross-reaction with human Hsp60 and im-mune complex formation.Two different situations appear clearly: the in-

vasion by the pathogen with acute inflammatoryhost response and the persistent infection with a

chronic permanent inflammation and tissue dam-age. What bears evidence is the presence of chla-mydial antigens, Hsps, DNA, and RNA in diseasedtissue preparations, especially submucosae pro-cessed with histologic techniques,s Those tissuesare usually culture negative, though, unless instraining conditions where nutrients are carefullyadded by multiple passages.6 We know that Hspsare sufficient to activate T cells and promote TH1cytokines. We also know that delayed hypersensi-tivity and autoimmunity to human Hsp60 inducelymphocyte and macrophage proliferation withtoxic products emission that concurs with fibrosisand necrosis. Genital infection is not such a goodmodel of persistent infection as trachoma, in whichscarring and blindness can be observed. However,as with trachoma, alteration of tissues leading to

functional impairment occurs after a previous in-fection and without any sign other than the pres-ence of nucleic acids, membrane antigens, andstress proteins. Moreover, many works have longassociated tissue scarring with permanent inflam-mation and delayed hypersensitivity due to auto-

immunity to self-Hsps,z3 Immunomodulation withtumor necrosis factor-or (TNF-ot), Hsp60 or 70, andmajor histocompatibility complex class-I genes

makes sense when their chromosomal proximityis considered. Consistent with that assessment,

mRNA for TNF-ot and interleukins (IL) and 6has been found in tubal tissues from patients with

ectopic pregnancy and tubal infertility.6,z This

finding proved that viable chlamydiae were thereand were associated with inflammation. Anotherwork even demonstrated that chlamydiae culti-vated in macrophages from joint tissue of a Reiter

syndrome patient infected long ago became infec-tious again. 7

Those works demonstrated the subclinical or

asymptomatic presence of chlamydiae in an incom-

plete, debilitated form capable of inducing inflam-mation and thus necrosis and fibrosis under certainconditions. From in vitro models, we could assume

that "persistent" chlamydiae could be responsiblefor that particular physiopathology. But, they couldalso be the inactive witnesses of the harm alreadydone by the active infection. However, the pres-ence of mRNA in the tissues, and the power ofneoactivation into active infection, pledge for liv-

ing but quiescent material.What do we learn from recent in vitro stud-

ies?8,zs Several factors inhibit the normal develop-ment cycle of Chlamydia: host cell cytokines (inter-feron-y with the mediation of TNF-ot), antibioticslike penicillin, ampicillin, and chlortetracycline.Cyclic nucleotides like cyclic adenosine mono-

phosphate (cAMP) and deprivation of nutrients

like tryptophan and cysteine impair the synthesisof the elementary bodies (EBS) membrane outer

membrane proteins and thus the cell division anddifferentiation of the reticulate bodies (RBS) thatremain large and atypical. To date such aberrantRBS have not been identified in vivo, but condi-tions of their presence could easily be reached in a

natural infection: cytokine emission from the host,humoral anti-major outer membrane protein anti-bodies with a partial protective effect to the hostcell, and deprived nutrient factors in deep tissueswith altered cell membrane functions. Antibioticslike penicillin or ampicillin used for other infec-tions can induce persistent forms. Tetracycline can

reverse the bactericidal effect if administered at

the wrong stage of the cycle. Moreover, those ad-verse conditions induce a progressive disappear-ance of the membrane proteins and an increase ofstress proteins which, as in other bacteria, contrib-ute to the loss of susceptibility to antimicrobial

32 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY


agents. This observation is consistent with theclinical inadequacy of classical treatments inchronic infections. However, we do not knowwhether this decreased susceptibility is due to theantimicrobial itself or to the alterations of the mem-brane.

CONCLUSIONAre silent genital chlamydial infections due to per-sistent forms of Chlamydia? The nucleic acids,Hsps, and antigens recognized in diseased tissuesthat are culture negative for Chlamydia are suffi-cient proof of immune stimulation and chronic ac-

tive disease. Persistent forms are admitted as stress

response forms capable of living again under favor-able circumstances. Removal of factors inducingpersistence can reactivate resolved infections un-der immunosuppressive conditions: coinfectionwith N. gonorrhoeae or environmental factors likehormones or vaginal flora. But, the consequence ofa blocked development cycle does not offer a pos-sibility of chemotherapy for these infections. Per-sistent abnormal forms must be recognized in vivobefore the clinical features of silent infections can

be assimilated to the cell-culture model of persis-tent chlamydiae. Persistence, thus chronic disease,might not occur after a well-treated uncomplicatedcervical infection. It is therefore important to rec-

ognize the risk for chronicity at the onset of aninfection. Anti- major outer membrane protein andanti-lipopolysaccharidc antibodies could go unde-tected in a chronic infection, so anti-C Hsp60 an-tibodies should be routinely processed when a

chronic infection is suspected in cases of tubal in-fertility or when in vitro fertilization fails. Treat-ment of persistent silent diseases and resolution ofchronic infection should be improved by more

knowledge of persistent infection.

REFERENCES1. Lehtinen M, Paavonen J. Heat shock proteins in the

immunopathogenesis of chlamydial pelvic inflammatorydisease. Proceedings of the 8th International Sympo-sium on Human Chlamydial Infections, Orfila J, ByrneG, Chernesky MA, et al (eds). Monvillargeney, France,1994, p 599-610.

2. Henry-Suchet J, Utzmann C, De Brux J, et al. Micro-biologic study of chronic inflammation associated withtubal factor infertility: Role of Chlamydia trachomatis.Fertil Steril 1987;47:274-277.

3. Henry-Suchet J, Askienazy-Elbhar M, Thibon M, et al.Post therapeutic evolution of serum chlamydial anti-

body titers in women with acute salpingitis and tubal

infertility. Fertil Steril 1994;62:296-304.

4. Kiviat NB, Wolner-Hanssen, Peterson M, et al. Local-ization of Chlamydia trachomatis infection by direct im-munofluorescenc and culture in pelvic inflammatorydisease. Am J Obstet Gynecol 1986;154:865-873.

5. Patton DL, Askienazy-Elbhar M, Henry-Suchet J, et al.Detection of Chlamydia trachomatis in fallopian tube tis-sue in women with postinfectious tubal infertility. Am JObstet Gynecol 1994;171:95-101.

6. Patton DL. Immune responses to C. trachomatis infec-tions in a non human primate model. Infect Dis ObstetGynecol 1996;4:159-162.

7. K6hler L, Nettelnbreker E, Zeidler H, et al. Persistenceof Chlamydia trachomatis serovar K in a non culturablebut metabolically active state in human peripheral bloodmonocytes. Proceedings of the 3rd meeting of the Eu-ropean Society for Chlamydia Research, Stary (ed.),1996;3:331.

8. Beatty WL, Morrison RP, Byrne GI. Persistent chla-mydiae: From cell culture to a paradigm for chlamydialpathogenesis. Microbiol Rev 1994;58:686-699.

9. Brunham RC, MacLean IW, Binns B, et al. Chlamydiatrachomatis: its role in tubal infertility. J Infect Dis 1985;152:1275-1282.

10. Morrison RP, Lyng K, Caldwell HD. Chlamydial dis-ease pathogenesis. Ocular hypersensitivity elicited by a

genus specific 57 kD protein. J Exp Med 1989;169:663-675.

11. Witkin SS, Jeremias J, Toth M, et al. Cell mediatedimmune response to the recombinant 57 kDa heatshock protein of Chlamydia trachomatis in women with

salpingitis. J Infect Dis 1993;167:1379-1383.

12. Arno JN, Yuan Y, Clcary RE, et al. Serologic responsesof infertile women to the 60 kD chlamydial heat shockprotein (hsp 60). Fertil Steril 1995;64:730-735.

13. Morrison RP, Manning DS, Caldwell HD. Immunologyof Chlamydia trachomatis infections. Immunoprotectiveand immunopathogenetic responses. In: Quinn TC(ed): Sexually Transmitted Diseases. New York: RavenPress, 1992, p 57-84.

14. Witkin SS, Sultan KM, Neal GS, ct al. Unsuspectedchlamydial infection and in vitro fertilization outcome.

Am J Obstet Gynecol 1994;171:1208-1214.

15. Askienazy-Elbhar M. Immune consequences of chla-mydial infections in pregnancy and in vitro fertilizationoutcome. Infect Dis Obstet Gynecol 1996;4:143-148.

16. Askienazy-Elbhar M, Moncan T, Orfila J, et al. Culturesde pr61vements pclviens dans des chlamydioses aigtiesou chroniques. Etude des s6rotypes obtenus. Proceed-ings of the 6th International Symposium on SexuallyTransmitted Diseases Research meeting, Banff,Canada, 1991.

17. Toye B, Laferri6re C, Claman P, et al. Association be-tween the chlamydial heat shock protein and tubal in-fertility. J Infect Dis 1993;168:1236-1240.

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 33


18. Paavonen J. Pelvic inflammatory disease: A global medi-cal emergency. Proceedings of the 12th InternationalSymposium on Sexually Transmitted Diseases Re-search meeting, Seville, Spain, 1997.

19. Stamm WE. Pathogenesis of pelvic inflammatory dis-ease. Proceedings of the 12th International Symposiumon Sexually Transmitted Diseases Research meeting,Seville, Spain, 1997.

20. Patton DL, Kuo CC, Wang SP, et al. Distal tubal ob-struction induced by repeated Chlamydia trachomatis sal-pingeal infections in pig-tailed macaques. J Infect Dis1987; 155:1292-1299.

21. Lichtenwalner AB, Patton DL, Cosgrove SJ, et al. MHCClass-I alleles associated with relative susceptibility to

pelvic inflammatory disease in Chlamydia trachomatis-infected macaques. Proceedings of the 3rd meeting of

the European Society for Chlamydia Research, Staryed., 1996;3:104.

22. Morrison RP. Immune protection against Chlamydia tra-

chomatis in females. Infect Dis Obstet Gynecol 1996;4:163-170.

23. Schachter J. Chlamydial infections. N Engl J Med 1978;298:428-435.

24. Gerard HC, Branigan PJ, Minassian SS, et al. Viability ofinapparent Chlamydia trachomatis in fallopian tubes ofectopic pregnancies. Proceedings of the 3rd meeting ofthe European Society for Chlamydia Research, Stary(ed.), 1996;3:296.

25. Beatty WL, Byrne GI, Morrison RP. Repeated and per-sistent infection with Chlamydia and the developmentof chronic inflammation and disease. Trends Microbiol1994;95:2;3.

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Persistent Chlamydia Female Genital Tractdownloads.hindawi.com/journals/idog/1999/264824.pdfG, CherneskyMA,et al (eds). Monvillargeney, France, 1994, p 599-610. 2. Henry-Suchet J,

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