Abstract
Human papillomaviruses (HPVs) are oncogenic viruses causing most cervical cancers. Highly prevalent in young, sexually active women, only a minority of HPV infections persist. To better characterize the immuno-modulatory impact of early HPV infections, we measured changes in a panel of 20 cytokines in cervicovaginal samples collected from young women who were tested for HPV and self-reported for genital inflammation and infection symptoms. Multi-factor statistical analyses revealed that increased IL-1Alpha and IL-12/IL-23p40 concentrations were associated with HPV infection and that macrophage inflammatory proteins were associated in particular with high-risk HPV infections. ClinicalTrials.gov identifier NCT02946346
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The data will be deposited at the Zenodo repository. https://zenodo.org/record/4701172.
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The R code for the statistical analysis will be deposited at the Zenodo repository.
References
de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141:664–70. https://doi.org/10.1002/ijc.30716.
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890–907. https://doi.org/10.1016/S0140-6736(07)61416-0.
Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, Solomon D, Burk R. Proyecto Epidemiológico Guanacaste Group, Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008;100:513–7. https://doi.org/10.1093/jnci/djn044.
IARC working group on the evaluation of carcinogenic risks to humans: occupational exposures of hairdressers and barbers and personal use of hair colourants; some hair dyes, cosmetic colourants, industrial dyestuffs and aromatic amines. Proceedings. Lyon, France, 6-13 October 1992. IARC Monogr Eval Carcinog Risks Hum. 1993; 57:7–398.
Steinbach A, Riemer AB. Immune evasion mechanisms of human papillomavirus: An update. Int J Cancer. 2018;142:224–9. https://doi.org/10.1002/ijc.31027.
Nasu K, Narahara H. Pattern recognition via the toll-like receptor system in the human female genital tract. Mediators Inflamm. 2010; (2010). https://doi.org/10.1155/2010/976024.
Amador-Molina A, Hernández-Valencia JF, Lamoyi E, Contreras-Paredes A, Lizano M. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses. 2013;5:2624–42. https://doi.org/10.3390/v5112624.
Nunes RAL, Morale MG, Silva GÁF, Villa LL, Termini L. Innate immunity and HPV: friends or foes. Clinics (Sao Paulo). 2018;73:e549s. https://doi.org/10.6061/clinics/2018/e549s.
Stanley M. Immunology of HPV Infection. Curr Obstet Gynecol Rep. 2015;4:195–200. https://doi.org/10.1007/s13669-015-0134-y.
Leone P, Shin E-C, Perosa F, Vacca A, Dammacco F, Racanelli V. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105:1172–87. https://doi.org/10.1093/jnci/djt184.
Alizon S, Murall CL, Bravo IG. Why Human Papillomavirus Acute Infections Matter. Viruses. 2017;9:293. https://doi.org/10.3390/v9100293.
Murall CL, Rahmoun M, Selinger C, Baldellou M, Bernat C, Bonneau M, Boué V, Buisson M, Christophe G, D’Auria G, Taroni FD, Foulongne V, Froissart R, Graf C, Grasset S, Groc S, Hirtz C, Jaussent A, Lajoie J, Lorcy F, Picot E, Picot M-C, Ravel J, Reynes J, Rousset T, Seddiki A, Teirlinck M, Tribout V, Tuaillon É, Waterboer T, Jacobs N, Bravo IG, Segondy M, Boulle N, Alizon S. Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study. BMJ Open. 2019;9:e025129. https://doi.org/10.1136/bmjopen-2018-025129.
Murall CL, Reyné B, Selinger C, Bernat C, Boué V, Grasset S, Groc S, Rahmoun M, Bender N, Bonneau M, Foulongne V, Graf C, Picot E, Picot M-C, Tribout V, Waterboer T, Bravo IG, Reynes J, Segondy M, Boulle N, Alizon S. HPV cervical infections and serological status in vaccinated and unvaccinated women. Vaccine. 2020;38:8167–74. https://doi.org/10.1016/j.vaccine.2020.10.078.
Dunn J, Wild D. Chapter 3.6 - Calibration Curve Fitting. In: Wild D, editors. The Immunoassay Handbook, 4th ed. Oxford: Elsevier; 2013.p. 323–336. https://doi.org/10.1016/B978-0-08-097037-0.00022-1.
O’Connell MA, Belanger BA, Haaland PD. Calibration and assay development using the four-parameter logistic model. Chemom Intell Lab Syst. 1993;20:97–114. https://doi.org/10.1016/0169-7439(93)80008-6.
Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N, Darragh TM, Brescia R, Kanowitz S, Miller SB, Stone J, Hanson E, Palefsky J. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277–84. https://doi.org/10.1016/s0022-3476(98)70445-7.
Zanotta N, Tornesello ML, Annunziata C, Stellato G, Buonaguro FM, Comar M. Candidate soluble immune mediators in young women with high-risk human papillomavirus infection: high expression of chemokines promoting angiogenesis and cell proliferation. PLoS One. 2016;11:e0151851. https://doi.org/10.1371/journal.pone.0151851.
Tummers B, Van Der Burg SH. High-risk human papillomavirus targets crossroads in immune signaling. Viruses. 2015;7:2485–506. https://doi.org/10.3390/v7052485.
Fernandes APM, Gonçalves MAG, Duarte G, Cunha FQ, Simões RT, Donadi EA. HPV16, HPV18, and HIV infection may influence cervical cytokine intralesional levels. Virology. 2005;334:294–8. https://doi.org/10.1016/j.virol.2005.01.029.
Liebenberg LJP, McKinnon LR, Yende-Zuma N, Garrett N, Baxter C, Kharsany ABM, Archary D, Rositch A, Samsunder N, Mansoor LE, Passmore J-AS, AbdoolKarim SS, AbdoolKarim Q. HPV infection and the genital cytokine milieu in women at high risk of HIV acquisition. Nat Commun. 2019;10:5227. https://doi.org/10.1038/s41467-019-13089-2.
Shannon B, Yi TJ, Perusini S, Gajer P, Ma B, Humphrys MS, Thomas-Pavanel J, Chieza L, Janakiram P, Saunders M, Tharao W, Huibner S, Shahabi K, Ravel J, Rebbapragada A, Kaul R. Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol. 2017;10:1310–9. https://doi.org/10.1038/mi.2016.129.
Moscicki A-B, Shi B, Huang H, Barnard E, Li H. Cervical-vaginal microbiome and associated cytokine profiles in a prospective study of HPV 16 acquisition, persistence, and clearance. Front Cell Infect Microbiol. (2020); 10. https://doi.org/10.3389/fcimb.2020.569022.
Jespers V, Hardy L, Buyze J, Loos J, Buvé A, Crucitti T. Association of sexual debut in adolescents with microbiota and inflammatory markers. Obstet Gynecol. 2016;128:22–31. https://doi.org/10.1097/AOG.0000000000001468.
Ghosh M, Jais M, Biswas R, Jarin J, Daniels J, Joy C, Juzumaite M, Emmanuel V, Gomez-Lobo V. Immune biomarkers and anti-HIV activity in the reproductive tract of sexually active and sexually inactive adolescent girls. Am J Reprod Immunol. 2018;79:e12846. https://doi.org/10.1111/aji.12846.
Boily-Larouche G, Lajoie J, Dufault B, Omollo K, Cheruiyot J, Njoki J, Kowatsch M, Kimani M, Kimani J, Oyugi J, Fowke KR. Characterization of the genital mucosa immune profile to distinguish phases of the menstrual cycle: implications for HIV susceptibility. J Infect Dis. 2019;219:856–66. https://doi.org/10.1093/infdis/jiy585.
Kanai T, Fukuda-Miki M, Shimoya K, Azuma C, Hashimoto K, Nobunaga T, Tokugawa Y, Tsujimoto M, Saji F, Murata Y. Increased interleukin-1 and interleukin-1 receptor antagonist levels in cervical mucus in the ovulatory phase in comparison with the follicular phase. Gynecol Obstet Invest. 1997;43:166–70. https://doi.org/10.1159/000291847.
Gosmann C, Mattarollo SR, Bridge JA, Frazer IH, Blumenthal A. IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia. J Immunol. 2014;193:2248–57. https://doi.org/10.4049/jimmunol.1400216.
Hede DV, Polese B, Humblet C, Wilharm A, Renoux V, Dortu E, de Leval L, Delvenne P, Desmet CJ, Bureau F, Vermijlen D, Jacobs N. Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation. PNAS. 2017;114:E9056–65. https://doi.org/10.1073/pnas.1712883114.
Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, Oppenheim JJ. Many chemokines including CCL20/MIP-3α display antimicrobial activity. J Leukoc Biol. 2003;74:448–55. https://doi.org/10.1189/jlb.0103024.
Belay T, Eko FO, Ananaba GA, Bowers S, Moore T, Lyn D, Igietseme JU. Chemokine and chemokine receptor dynamics during genital chlamydial infection. Infect Immun. 2002;70:844–50. https://doi.org/10.1128/IAI.70.2.844-850.2002.
Poston TB, Lee DE, Darville T, Zhong W, Dong L, O’Connell CM, Wiesenfeld HC, Hillier SL, Sempowski GD, Zheng X. Cervical cytokines associated with chlamydia trachomatis susceptibility and protection. J Infect Dis. 2019;220:330–9. https://doi.org/10.1093/infdis/jiz087.
Radomski N, Karger A, Franzke K, Liebler-Tenorio E, Jahnke R, Matthiesen S, Knittler MR. Chlamydia psittaci-infected dendritic cells communicate with NK cells via exosomes to activate antibacterial immunity. Infect Immun. 2019; 88. https://doi.org/10.1128/IAI.00541-19.
Gillet E, Meys JF, Verstraelen H, Bosire C, De Sutter P, Temmerman M, Broeck DV. Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis. BMC Infect Dis. 2011;11:10. https://doi.org/10.1186/1471-2334-11-10.
De Seta F, Campisciano G, Zanotta N, Ricci G, Comar M. The vaginal community state types microbiome-immune network as key factor for bacterial vaginosis and aerobic vaginitis. Front Microbiol. 2019;10:2451. https://doi.org/10.3389/fmicb.2019.02451.
Masson L, Mlisana K, Little F, Werner L, Mkhize NN, Ronacher K, Gamieldien H, Williamson C, Mckinnon LR, Walzl G, AbdoolKarim Q, AbdoolKarim SS, Passmore J-AS. Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study. Sex Transm Infect. 2014;90:580–7. https://doi.org/10.1136/sextrans-2014-051601.
Selinger C, Tisoncik-Go J, Menachery VD, Agnihothram S, Law GL, Chang J, Kelly SM, Sova P, Baric RS, Katze MG. Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates. BMC Genomics. 2014;15:1161. https://doi.org/10.1186/1471-2164-15-1161.
Elovitz MA, Gajer P, Riis V, Brown AG, Humphrys MS, Holm JB, Ravel J. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat Commun. 2019;10:1305. https://doi.org/10.1038/s41467-019-09285-9.
Acknowledgements
The authors acknowledge the IRD itrop HPC (South Green Platform) at IRD Montpellier for providing HPC resources that have contributed to the research results reported within this paper (URL: http://www.southgreen.fr).
We also acknowledge productive feedback on the manuscript by Nicolas Tessandier.
Funding
This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program [grant agreement No 648963 to SA]. The sponsor had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.
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Conceived or designed the study: SA, CLM, CH, NJ, and JR.
Wrote the paper: SA, CS, MR, CLM, and NJ.
Performed research: MR, CB, VB, Soraya G, SG, CG, and MB.
Contributed new methods or models: CS and MR.
Analyzed data: CS.
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Selinger, C., Rahmoun, M., Murall, C.L. et al. Cytokine response following perturbation of the cervicovaginal milieu during HPV genital infection. Immunol Res 69, 255–263 (2021). https://doi.org/10.1007/s12026-021-09196-2
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DOI: https://doi.org/10.1007/s12026-021-09196-2