Aberrant cervical innate immunity predicts onset of dysbiosis and sexually transmitted infections in women of reproductive age
Autoři:
Raina N. Fichorova aff001; Charles S. Morrison aff002; Pai-Lien Chen aff003; Hidemi S. Yamamoto aff001; Yashini Govender aff001; Damilola Junaid aff001; Stanthia Ryan aff001; Cynthia Kwok aff003; Tsungai Chipato aff004; Robert A. Salata aff005; Gustavo F. Doncel aff006
Působiště autorů:
Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States of America
aff001; Behavioral, Epidemiologic and Clinical Sciences, FHI, Durham, NC, United States of America
aff002; Biostatistics, FHI, Durham, NC, United States of America
aff003; University of Zimbabwe, Harare, Zimbabwe
aff004; Case Western Reserve University, Cleveland, OH, United States of America
aff005; CONRAD, Arlington, VA, United States of America
aff006; Eastern Virginia Medical School, Norfolk, VA, United States of America
aff007
Vyšlo v časopise:
PLoS ONE 15(1)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0224359
Souhrn
Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4–6) or high (7–10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5–4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of β-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1β–to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI–to candida, lower levels of the adhesion molecule ICAM-1 –to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF–to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.
Klíčová slova:
HIV – Innate immune system – Immune response – Immunity – Sexually transmitted diseases – Biomarkers – Microbiome – Candida
Zdroje
1. Buve A, Jespers V, Crucitti T, Fichorova RN. The vaginal microbiota and susceptibility to HIV. AIDS. 2014;28(16):2333–44. doi: 10.1097/qad.0000000000000432 25389548.
2. Kim HS, Kim TJ, Lee IH, Hong SR. Associations between sexually transmitted infections, high-risk human papillomavirus infection, and abnormal cervical Pap smear results in OB/GYN outpatients. J Gynecol Oncol. 2016;27(5):e49–e. Epub 2016/05/16. doi: 10.3802/jgo.2016.27.e49 27329197.
3. Onderdonk AB, Delaney ML, Fichorova RN. The Human Microbiome during Bacterial Vaginosis. Clin Microbiol Rev. 2016;29(2):223–38. doi: 10.1128/CMR.00075-15 26864580; PubMed Central PMCID: PMC4786887.
4. Tsevat DG, Wiesenfeld HC, Parks C, Peipert JF. Sexually transmitted diseases and infertility. American journal of obstetrics and gynecology. 2017;216(1):1–9. doi: 10.1016/j.ajog.2016.08.008 28007229.
5. Murphy K, Irvin SC, Herold BC. Research gaps in defining the biological link between HIV risk and hormonal contraception. American journal of reproductive immunology. 2014;72(2):228–35. doi: 10.1111/aji.12209 24548147; PubMed Central PMCID: PMC4106985.
6. Masson L, Passmore JA, Liebenberg LJ, Werner L, Baxter C, Arnold KB, et al. Genital inflammation and the risk of HIV acquisition in women. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2015;61(2):260–9. doi: 10.1093/cid/civ298 25900168; PubMed Central PMCID: PMC4565995.
7. UN. Trends in Contraceptive Use Worldwide. Department of Economic & Social Affairs. Population Division. New York: United Nations; 2015.
8. Kharsany AB, Karim QA. HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities. The open AIDS journal. 2016;10:34–48. doi: 10.2174/1874613601610010034 27347270; PubMed Central PMCID: PMC4893541.
9. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN, et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. Aids. 2016;30(17):2665–83. doi: 10.1097/QAD.0000000000001228 27500670; PubMed Central PMCID: PMC5106090.
10. Hofmeyr GJ, Morrison CS, Baeten JM, Chipato T, Donnell D, Gichangi P, et al. Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study). Gates Open Research. 1018;1:1–17. doi: 10.12688/gatesopenres.12756.1
11. Consortium EfCOaHOET. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019. Epub Jun 13.
12. Morrison C, Fichorova RN, Mauck C, Chen PL, Kwok C, Chipato T, et al. Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion. J Acquir Immune Defic Syndr. 2014;66(2):109–17. doi: 10.1097/QAI.0000000000000103 24413042.
13. Fichorova RN, Chen PL, Morrison CS, Doncel GF, Mendonca K, Kwok C, et al. The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception. MBio. 2015;6(5):e00221–15. doi: 10.1128/mBio.00221-15 26330510; PubMed Central PMCID: PMC4556810.
14. Morrison CS, Chen PL, Kwok C, Richardson BA, Chipato T, Mugerwa R, et al. Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling. AIDS. 2010;24(11):1778–81. Epub 2010/07/01. doi: 10.1097/QAD.0b013e32833a2537 20588106; PubMed Central PMCID: PMC3148067.
15. Morrison CS, Fichorova R, Chen PL, Kwok C, Deese J, Yamamoto H, et al. A Longitudinal Assessment of Cervical Inflammation and Immunity Associated with HIV-1 Infection, Hormonal Contraception, and Pregnancy. AIDS Res Hum Retroviruses. 2018;34(10):889–99. doi: 10.1089/AID.2018.0022 30047279; PubMed Central PMCID: PMC6204564.
16. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J, et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. Epub 2006/12/07. doi: 10.1097/QAD.0b013e3280117c8b 17148972.
17. Van Der Pol B, Kwok C, Pierre-Louis B, Rinaldi A, Salata RA, Chen PL, et al. Trichomonas vaginalis infection and human immunodeficiency virus acquisition in African women. The Journal of infectious diseases. 2008;197(4):548–54. doi: 10.1086/526496 18275275.
18. van de Wijgert JH, Morrison CS, Cornelisse PG, Munjoma M, Moncada J, Awio P, et al. Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women. J Acquir Immune Defic Syndr. 2008;48(2):203–10. doi: 10.1097/QAI.0b013e3181743936 18520679.
19. Mauck C, Chen PL, Morrison CS, Fichorova RN, Kwok C, Chipato T, et al. Biomarkers of Cervical Inflammation and Immunity Associated with Cervical Shedding of HIV-1. AIDS Res Hum Retroviruses. 2016;32(5):443–51. doi: 10.1089/AID.2015.0088 26650885; PubMed Central PMCID: PMC4845652.
20. Fichorova RN. Guiding the vaginal microbicide trials with biomarkers of inflammation. J Acquir Immune Defic Syndr. 2004;37 Suppl 3:S184–93. 16419271; PubMed Central PMCID: PMC2643374.
21. Schwartz JL, Mauck C, Lai JJ, Creinin MD, Brache V, Ballagh SA, et al. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception. 2006;74(2):133–40. doi: 10.1016/j.contraception.2006.02.008 16860051.
22. Barker L, Rolka H, Rolka D, Brown C. Equivalence testing for binomial random variables: which test to use? American Statistician. 2001;55:279–87.
23. Alcaide ML, Rodriguez VJ, Brown MR, Pallikkuth S, Arheart K, Martinez O, et al. High Levels of Inflammatory Cytokines in the Reproductive Tract of Women with BV and Engaging in Intravaginal Douching: A Cross-Sectional Study of Participants in the Women Interagency HIV Study. AIDS Res Hum Retroviruses. 2017;33(4):309–17. doi: 10.1089/AID.2016.0187 27897054; PubMed Central PMCID: PMC5372759.
24. Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42(5):965–76. doi: 10.1016/j.immuni.2015.04.019 25992865; PubMed Central PMCID: PMC4461369.
25. Birse KD, Romas LM, Guthrie BL, Nilsson P, Bosire R, Kiarie J, et al. Genital Injury Signatures and Microbiome Alterations Associated With Depot Medroxyprogesterone Acetate Usage and Intravaginal Drying Practices. The Journal of Infectious Diseases. 2017;215(4):590–8. doi: 10.1093/infdis/jiw590 PMC5388302. 28011908
26. Raj PA, Dentino AR. Current status of defensins and their role in innate and adaptive immunity. FEMS Microbiology Letters. 2002;206(1):9–18. doi: 10.1111/j.1574-6968.2002.tb10979.x 11786250
27. Alfano M, Poli G. Role of cytokines and chemokines in the regulation of innate immunity and HIV infection. Molecular immunology. 2005;42(2):161–82. doi: 10.1016/j.molimm.2004.06.016 15488606.
28. Buckley N, Huber A, Lo Y, Castle PE, Kemal K, Burk RD, et al. Association of High-Risk Human Papillomavirus with Genital Tract Mucosal Immune Factors in HIV-Infected Women. American journal of reproductive immunology. 2016;75(2):146–54. doi: 10.1111/aji.12461 26685115; PubMed Central PMCID: PMC4715979.
29. Borish LC, Steinke JW. 2. Cytokines and chemokines. The Journal of allergy and clinical immunology. 2003;111(2 Suppl):S460–75. doi: 10.1067/mai.2003.108 12592293.
30. Appay V, Rowland-Jones SL. RANTES: a versatile and controversial chemokine. Trends in immunology. 2001;22(2):83–7. doi: 10.1016/s1471-4906(00)01812-3 11286708.
31. Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infection and immunity. 2005;73(3):1271–4. doi: 10.1128/IAI.73.3.1271-1274.2005 15731023.
32. Fichorova RN, Lee Y, Yamamoto HS, Takagi Y, Hayes GR, Goodman RP, et al. Endobiont viruses sensed by the human host—beyond conventional antiparasitic therapy. PLoS One. 2012;7(11):e48418. doi: 10.1371/journal.pone.0048418 23144878; PubMed Central PMCID: PMC3492353.
33. Africander D, Louw R, Verhoog N, Noeth D, Hapgood JP. Differential regulation of endogenous pro-inflammatory cytokine genes by medroxyprogesterone acetate and norethisterone acetate in cell lines of the female genital tract. Contraception. 2011;84(4):423–35. doi: 10.1016/j.contraception.2011.06.006 21920200.
34. Govender Y, Avenant C, Verhoog NJ, Ray RM, Grantham NJ, Africander D, et al. The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor. PloS one. 2014;9(5):e96497. doi: 10.1371/journal.pone.0096497 24840644; PubMed Central PMCID: PMC4026143.
35. Hapgood JP, Ray RM, Govender Y, Avenant C, Tomasicchio M. Differential glucocorticoid receptor-mediated effects on immunomodulatory gene expression by progestin contraceptives: implications for HIV-1 pathogenesis. American journal of reproductive immunology. 2014;71(6):505–12. doi: 10.1111/aji.12214 24547700.
36. Louw-du Toit R, Hapgood JP, Africander D. Medroxyprogesterone acetate differentially regulates interleukin (IL)-12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR)-dependent manner. The Journal of biological chemistry. 2014;289(45):31136–49. doi: 10.1074/jbc.M114.587311 25202013; PubMed Central PMCID: PMC4223317.
37. Huijbregts RP, Michel KG, Hel Z. Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs. Contraception. 2014;90(2):123–9. doi: 10.1016/j.contraception.2014.02.006 24674041; PubMed Central PMCID: PMC4874781.
38. Koubovec D, Ronacher K, Stubsrud E, Louw A, Hapgood JP. Synthetic progestins used in HRT have different glucocorticoid agonist properties. Molecular and cellular endocrinology. 2005;242(1–2):23–32. doi: 10.1016/j.mce.2005.07.001 16125839.
39. Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34(2):171–208. doi: 10.1210/er.2012-1008 23238854; PubMed Central PMCID: PMC3610676.
40. Patel MV, Fahey JV, Rossoll RM, Wira CR. Innate immunity in the vagina (part I): estradiol inhibits HBD2 and elafin secretion by human vaginal epithelial cells. Am J Reprod Immunol. 2013;69(5):463–74. doi: 10.1111/aji.12078 23398087; PubMed Central PMCID: PMC3837349.
41. Achilles SL, Mhlanga FG, Musara P, Poloyac SM, Chirenje ZM, Hillier SL. Misreporting of contraceptive hormone use in clinical research participants. Contraception. 2018;97(4):346–53. doi: 10.1016/j.contraception.2017.09.013 PMC5858917. 28966052
42. Rothman KJ. Six persistent research misconceptions. J Gen Intern Med. 2014;29(7):1060–4. Epub 2014/01/24. doi: 10.1007/s11606-013-2755-z 24452418; PubMed Central PMCID: PMC4061362.
43. CDC. https://www.cdc.gov/std/tg2015/trichomoniasis.htm 2019 [cited 2019].
44. Schwebke JR, Gaydos CA, Nyirjesy P, Paradis S, Kodsi S, Cooper CK. Diagnostic Performance of a Molecular Test versus Clinician Assessment of Vaginitis. Journal of Clinical Microbiology. 2018;56(6):e00252–18. doi: 10.1128/JCM.00252-18 29643195
45. Workowski KA, Bolan GA, Centers for Disease C, Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. 26042815.
46. Haimovici F, Anderson JL, Batesb GW, Racowsky C, Ginsburg E, Simovicic D, et al. Stress, anxiety and depression of both partners in infertile couples are associated with cytokine levels and adverse IVF outcome. American journal of reproductive immunology. 2018.
47. McKinnon LR, Liebenberg LJ, Yende-Zuma N, Archary D, Ngcapu S, Sivro A, et al. Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women. Nature Medicine. 2018. doi: 10.1038/nm.4506 29480895
48. Ramjee G, Williams B, Gouws E, Van Dyck E, De Deken B, Karim SA. The impact of incident and prevalent herpes simplex virus-2 infection on the incidence of HIV-1 infection among commercial sex workers in South Africa. Journal of acquired immune deficiency syndromes. 2005;39(3):333–9. doi: 10.1097/01.qai.0000144445.44518.ea 15980695.
49. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006;20(1):73–83. Epub 2005/12/06. doi: 10.1097/01.aids.0000198081.09337.a7 16327322.
50. McClelland RS, Sangare L, Hassan WM, Lavreys L, Mandaliya K, Kiarie J, et al. Infection with Trichomonas vaginalis increases the risk of HIV-1 acquisition. The Journal of infectious diseases. 2007;195(5):698–702. doi: 10.1086/511278 17262712.
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