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Contribution of Epithelial Cells to Defense Mechanisms in the Human Vagina

  • Iara M. LinharesEmail author
  • Giovanni Sisti
  • Evelyn Minis
  • Gabriela B. de Freitas
  • Antonio F. Moron
  • Steven S. Witkin
Female Genital Tract Infections (J Sobel, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Female Genital Tract Infections

Abstract

Purpose of Review

The vaginal milieu in women differs from that of other mammals, including non-human primates, in composition of secretions, the endogenous microbiota, and level of acidity. These changes apparently reflect evolutionary variations that maximized productive responses to a uniquely human vaginal environment. This review will highlight recent findings on properties of human vaginal epithelial cells that contribute to maintenance of a healthy vaginal environment.

Recent Findings

Vaginal epithelial cells are responsive to the composition of the vaginal microbiome even in women who are in apparently good health and do not exhibit any adverse physical symptoms. This is especially important during pregnancy when immune defenses are modified and an effective epithelial cell-derived anti-microbial activity is essential to prevent the migration to the uterus of bacteria potentially harmful to pregnancy progression. When Lactobacillus crispatus numerically predominates in the vagina, epithelial cell activity is low. Conversely, predominance of Lactobacillus iners, Gardnerella vaginalis, or other non-Lactobacilli evokes production and release of a large variety of compounds to minimize the potentially negative consequences of an altered microbiome. The extent of autophagy in vaginal epithelial cells, a basic process that functions to maintain intracellular homeostasis and engulf microbial invaders, is also sensitive to the external microbial environment Vaginal epithelial cells bind and release norepinephrine and upregulate their anti-microbial activity in response to external stress.

Summary

Vaginal epithelial cells in women are responsive to local conditions that are unique to humans and, thereby, contribute to maintenance of a healthy milieu.

Keywords

Autophagy Stress Vaginal epithelial cells Vaginal microbiome 

Notes

Compliance with Ethical Standards

Conflict of Interest

Iara M. Linhares, Giovanni Sisti, Evelyn Minis, Gabriela B. de Freitas, Antonio F. Moron, and Steven S. Witkin declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Witkin SS, Linhares IM. Why do lactobacilli dominate the human vaginal microbiota? BJOG. 2017;124:606–11. This article highlights and summarizes why Lactobacilli dominance in the vagina is unique to humans.CrossRefGoogle Scholar
  2. 2.
    Witkin SS, Ledger WJ. Complexities of the uniquely human vagina. Sci Transl Med. 2012;4:132fs11.CrossRefGoogle Scholar
  3. 3.
    Stumpf RM, Wilson BA, Rivera A, Yidirim S, Yeoman CJ, Polk JD, et al. The primate vaginal microbiome: comparative context and implications for human health and disease. Am J Phys Anthropol. 2013;152:119–34.CrossRefGoogle Scholar
  4. 4.
    Patton DL, Thwin SS, Meier A, Hooton TM, Stapleton AR, Eschenbach DA. Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. Am J Obstet Gynecol. 2000;183:967–73.CrossRefGoogle Scholar
  5. 5.
    Nasioudis D, Beghini J, Bongiovanni AM, Giraldo PC, Linhares IM. Witkin SS. α-amylase in vaginal fluid: association with conditions favorable to dominance of Lactobacillus. Reprod Sci. 2015;22(1):1393–8.  https://doi.org/10.1177/1933719115581000rs.sagepub.com.CrossRefPubMedGoogle Scholar
  6. 6.
    Spear GT, French AL, Gilbert D, Zariffard MR, Mirmonsef P, Sullivan TH, et al. Human α-amylase present in lower-genital-tract mucosal fluid processes glycogen to support vaginal colonization by Lactobacillus. J Infect Dis. 2014;210(7):1019–28.  https://doi.org/10.1093/infdis/jiu231.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    O’Hanlon DE, Moench TR, Cone RA. Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS One. 2013;8:e80074.CrossRefGoogle Scholar
  8. 8.
    Witkin SS, Mendes-Soares H, Linhares IM, Jayaram A, Ledger WJ, Forney LJ. Influence of vaginal bacteria and D- and L- lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections. mBio. 2013;4(4):e00460–13.CrossRefGoogle Scholar
  9. 9.
    O’Hanlon DE, Moench TR, Cone RA. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis. 2011;11:200.CrossRefGoogle Scholar
  10. 10.
    Alakomi HL, Skytta E, Saarela M, Mattila-Sandholm T, Latva-Kala K, Helander IM. Lactic acid permealizes Gram-negative bacteria by disrupting the outer membrane. Appl Environ Microbiol. 2000;66:2001–5.CrossRefGoogle Scholar
  11. 11.
    Wilson MC, Meredith D, Fox JE, Manoharan C, Davies AJ, Halestrap AP. Besigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4; the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem. 2005;280:27213–21.CrossRefGoogle Scholar
  12. 12.
    Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4680–7.CrossRefGoogle Scholar
  13. 13.
    Kelly RD, Cowley SM. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans. 2013;41:741–9.CrossRefGoogle Scholar
  14. 14.
    • Witkin SS, Nasioudis D, Leizer J, Minis E, Boester A, Forney LJ. Epigenetics and the vaginal microbiome: influence of the microbiota on the histone deacetylase level in vaginal epithelial cells from pregnant women. Minerva Ginecol. 2019;71:171–5.  https://doi.org/10.23736/S0026-4784.18.04322-8. This provides evidence that the vaginal microbiota exerts influence on vaginal epithelial cells by an epigenetic mechanism.CrossRefPubMedGoogle Scholar
  15. 15.
    Kindinger LM, Bennett PR, Lee YS, Marchesi JR, Smith A, Cacciatore S, et al. The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome. 2017;5(1):6.  https://doi.org/10.1186/s40168-016-0223-9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Callahan BJ, DiGiulio DB, Goltsman DSA, Sun CL, Costello EK, Jeganathan P, et al. Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. Proc Natl Acad Sci U S A. 2017;114(37):9966–71.  https://doi.org/10.1073/pnas.1705899114.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Asea A. Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev. 2005;11:34–45.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Powell JD, Horton MR. Threat matrix: low-molecular weight hyaluronan (HA) as a danger signal. Immunol Res. 2005;31:207–18.CrossRefGoogle Scholar
  19. 19.
    Lee J, Jang A, Kim JW, Han JH, Chun BH, Jung HS, et al. Distinct histone modifications modulate DEFB1 expression in human vaginal keratinocytes in response to Lactobacillus spp. Probiotics & Antimicro Prot. 2017;9:406–14.  https://doi.org/10.1007/s12602-017-9286-6.CrossRefGoogle Scholar
  20. 20.
    Beghini J, Giraldo PC, Linhares IM, Ledger WJ, Witkin SS. Neutrophil gelatinase- associated lipocalin concentration in vaginal fluid: relation to bacterial vaginosis and vulvovaginal candidiasis. Reprod Sci. 2015;22:964–8.CrossRefGoogle Scholar
  21. 21.
    Nasioudis D, Witkin SS. Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections. Med Microbiol Immunol. 2015;204:471–9.CrossRefGoogle Scholar
  22. 22.
    Jarosik GP, Land CB, Duhon P, Chandler R Jr, Mercer T. Acquisition of iron by Gardnerella vaginalis. Infect Immun. 1998;66:5041–7.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Inbert M, Blondeau R. On the iron requirement of lactobacilli grown in chemically defined medium. Curr Microbiol. 1998;37:64–6.CrossRefGoogle Scholar
  24. 24.
    Rein MF, Shih LM, Miller JR, Guerrant RL. Use of a lactoferrin assay in the differential diagnosis of female genital tract infections and implications for the pathophysiology of bacterial vaginosis. Sex Transm Dis. 1996;23:517–21.CrossRefGoogle Scholar
  25. 25.
    Kostakis ID, Cholidou KG, Kallianidis K, Perrea D, Antsaklis A. The role of calprotectin in obstetrics and gynecology. Eur J Obstet Gynecol Reprod Biol. 2010;151:3–9.CrossRefGoogle Scholar
  26. 26.
    Leizer J, Nasioudis D, Forney LJ, Schneider GM, Gliniewicz K, Boester A, et al. Properties of epithelial cells and vaginal secretions in pregnant women when. Lactobacillus crispatus or Lactobacillus iners dominate the vaginal microbiome. Reprod Sci. 2018;25(6):854–60.  https://doi.org/10.1177/1933719117698583.CrossRefPubMedGoogle Scholar
  27. 27.
    Vaneechoutte M. Lactobacillus iners, the unusual suspect. Res Microbiol. 2017;168(9–10):826–36.  https://doi.org/10.1016/j.resmic.2017.09.003.CrossRefPubMedGoogle Scholar
  28. 28.
    Draper DL, Landers DV, Krohn MA, Sl H, Wiesenfeld HC, Heine RP. Levels of vaginal secretory leukocyte protease inhibitor are decreased in women with lower reproductive tract infections. Am J Obstet Gynecol. 2000;183:1243–8.CrossRefGoogle Scholar
  29. 29.
    Bulla R, De Seta F, Radillo O, Agostinis C, Durigutto P, Pellis V, et al. Mannose- binding lectin is produced by vaginal epithelial cells and its level in the vaginal fluid is influenced by progesterone. Mol Immunol. 2010;48(1–3):281–6.  https://doi.org/10.1016/j.molimm.2010.07.016.CrossRefPubMedGoogle Scholar
  30. 30.
    Pivarcsi A, Nagy I, Koreck A, Kenderessy-Szabo A, Szell M, Dobozy A, et al. Microbial compounds induce the expression of pro-inflammatory cytokines, chemokines and human beta-defensin-2 in vaginal epithelial cells. Microbes Infect. 2005;7(9–10):1117–27.CrossRefGoogle Scholar
  31. 31.
    Cole AM. Innate host defense of human vaginal and cervical mucosae. Curr Top Microbial Immunol. 2006;306:199–230.Google Scholar
  32. 32.
    Fazeli A, Bruce C, Anumba DO. Characterization of Toll-like receptors in the female reproductive tract in humans. Hum Reprod. 2005;20:1372–8.CrossRefGoogle Scholar
  33. 33.
    Anderson DJ, Marathe J, Putney J. The structure of the human vaginal stratum corneum and its role in immune defense. Am J Reprod Immunol. 2014;71:618–23.CrossRefGoogle Scholar
  34. 34.
    Witkin SS. The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. BJOG. 2014;122:213–8.  https://doi.org/10.1111/1471-0528.13115.CrossRefPubMedGoogle Scholar
  35. 35.
    Aldunate M, Srbinovski D, Hearps AC, Latham CF, Ramsland PA, Gugasyan R, et al. Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis. Front Physiol. 2015;6:164.CrossRefGoogle Scholar
  36. 36.
    Jasarevic E, Howerton CL, Howrd CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinol. 2015;156(9):3265–76.  https://doi.org/10.1210/en.2015-1177.CrossRefGoogle Scholar
  37. 37.
    Brosnahan AJ, Vulchanova L, Witta SR, Dai Y, Jones BJ, Brown DR. Norepinephrine potentiates proinflammatory responses of human vaginal epithelial cells. J Neuroimmunol. 2013;259:8–16.  https://doi.org/10.1016/j.jneuroim.2013.03.005.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    •• Lyte M, Brown DR. Evidence for PMAT- and OCT-like biogenic amine transporters in a probiotic strain of Lactobacillus: implications for interkingdom communication within the microbiota-gut-brain axis. PLoS One. 2018;13(1):e0191037.  https://doi.org/10.1371/journal.pone.0191037. Recent evidence that Lactobacilli are responsive to stress hormones.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Amabebe E, Anumba DOC. Psychosocial stress, cortisol levels, and maintenance of vaginal health. Front Endocrinol. 2018;9:568.  https://doi.org/10.3389/fendo.2018.00568.CrossRefGoogle Scholar
  40. 40.
    Wang C-W, Klionsky DJ. The molecular mechanism of autophagy. Mol Med. 2003;9:65–76.CrossRefGoogle Scholar
  41. 41.
    Dokladny K, Myers OB, Mosley PL. Heat shock response and autophagy-cooperation and control. Autophagy. 2015;11:200–13.  https://doi.org/10.1080/15548627.2015.1009776.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988;22:631–77.CrossRefGoogle Scholar
  43. 43.
    Dokladny K, Zuhl MN, Mandell M, Bhattacharya D, Schneider S, Deretic V, et al. Regulatory coordination between two major intracellular homeostatic systems. Heat shock response and autophagy. J Biol Chem. 2013;288:14959–72.  https://doi.org/10.1074/jbc.M113.462408.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kanninen TT, Sisti G, Witkin SS. Induction of the 70kDa heat shock protein stress response inhibits autophagy: possible consequences for pregnancy outcome. J Matern Fetal Neonatal Med. 2016;29:159–62.CrossRefGoogle Scholar
  45. 45.
    • Nasioudis D, Forney LJ, Schneider GM, Gliniewicz K, France MT, Boester A, et al. The composition of the vaginal microbiome in first trimester pregnant women influences the level of autophagy and stress in vaginal epithelial cells. J Reprod Immunol. 2017;123:35–9.  https://doi.org/10.1016/j.jri.2017.08.009. The relationship between vaginal microbiome composition, stress and autophagy is highlighted.CrossRefPubMedGoogle Scholar
  46. 46.
    Ramos BR, Witkin SS. The influence of oxidative stress and autophagy cross regulation on pregnancy outcome. Cell Stress Chaperones. 2016;21:755–62.CrossRefGoogle Scholar
  47. 47.
    Fichorova R, Anderson DJ. Differential expression of immunobiological mediators by immortalize human cervical and vaginal epithelial cells. Biol Reprod. 1999;60:508–14.CrossRefGoogle Scholar
  48. 48.
    •• Shroff A, Sequeira R, Reddy KVR. Human vaginal epithelial cells augment autophagy marker genes in response to Candida albicans infection. Am J Reprod Immunol 2017;77(4):  https://doi.org/10.1111/aji.12639. Evidence that human vaginal epithelial cells defend against Candida albicans infection by induction of autophagy.CrossRefGoogle Scholar
  49. 49.
    Shroff A, Reddy KVR. Autophagy gene ATG5 knockdown upregulates apoptotic cell death during Candida albicans infection in human vaginal epithelial cells. Am J Reprod Immunol. 2018;80(6):e13056.  https://doi.org/10.1111/aji.13056.CrossRefPubMedGoogle Scholar
  50. 50.
    Scholl J, Nasioudis D, Boester SM, Grunebaum A, Witkin SS. Group B streptococcus alters properties of vaginal epithelial cells in pregnant women. Am J Obstet Gynecol. 2016;214(3):383.e1–5.  https://doi.org/10.1016/j.ajog.2015.12.053.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Iara M. Linhares
    • 1
    Email author
  • Giovanni Sisti
    • 2
  • Evelyn Minis
    • 2
  • Gabriela B. de Freitas
    • 1
  • Antonio F. Moron
    • 3
    • 4
  • Steven S. Witkin
    • 3
    • 5
  1. 1.Department of Gynecology and ObstetricsUniversity of Sao Paulo Medical SchoolSao PauloBrazil
  2. 2.Department of Obstetrics and GynecologyLincoln Medical and Mental Health CenterBronxUSA
  3. 3.Institute of Tropical MedicineUniversity of Sao Paulo Medical SchoolSao PauloBrazil
  4. 4.Department of ObstetricsFederal University of Sao PauloSao PauloBrazil
  5. 5.Department of Obstetrics and GynecologyWeill Cornell MedicineNew YorkUSA

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