{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T19:09:18Z","timestamp":1785179358438,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"Background<\/jats:title>Vaginal microbiome and the local innate immune defense, including the complement system, contribute to anti- and proinflammatory homeostasis during pregnancy and parturition. The relationship between commensal vaginal bacteria and complement activation during pregnancy and delivery is not known.<\/jats:p><\/jats:sec>Objective<\/jats:title>To study the association of the cervicovaginal microbiota composition to activation and regulation of the complement system during pregnancy and labor.<\/jats:p><\/jats:sec>Study design<\/jats:title>We recruited women during late pregnancy (weeks 41 + 5 to 42 + 0, n=48) and women in active labor (weeks 38 + 4 to 42 + 2, n=25). Mucosal swabs were taken from the external cervix and lateral fornix of the vagina. From the same sampling site, microbiota was analyzed with 16S RNA gene amplicon sequencing. A Western blot technique was used to detect complement C3, C4 and factor B activation and presence of complement inhibitors. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and staining intensities were analyzed using ImageJ\/Fiji win-64 software. Patient data was collected from medical records and questionnaires.<\/jats:p><\/jats:sec>Results<\/jats:title>The vaginal microbiota was Lactobacillus<\/jats:italic>-dominant in most of the samples (n=60), L. iners<\/jats:italic> and L. crispatus<\/jats:italic> being the dominant species. L. gasseri<\/jats:italic> and L. jensenii<\/jats:italic> were found to be more abundant during pregnancy than active labor. L. jensenii<\/jats:italic> abundance correlated with C4 activation during pregnancy but not in labor. Gardnerella vaginalis<\/jats:italic> was associated with C4 activation both during pregnancy and labor. The amount of L. gasseri<\/jats:italic> correlated with factor B activation during pregnancy but not during labor. Atopobium vaginae<\/jats:italic> was more abundant during pregnancy than labor and correlated with C4 activation during labor and with factor B activation during pregnancy. Activation of the alternative pathway factor B was significantly stronger during pregnancy compared to labor. During labor complement activation may be inhibited by the abundant presence of factor H and FHL1.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>These results indicate that bacterial composition of the vaginal microbiota could have a role in the local activation and regulation of complement-mediated inflammation during pregnancy. At the time of parturition complement activation appears to be more strictly regulated than during pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.925630","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T12:56:07Z","timestamp":1658753767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Cervicovaginal Complement Activation and Microbiota During Pregnancy and in Parturition"],"prefix":"10.3389","volume":"13","author":[{"given":"Sivan","family":"Livson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Virtanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Inkeri","family":"Lokki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina","family":"Holster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Rahkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkka","family":"Kalliala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka","family":"Nieminen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Salonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Meri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2010.67","article-title":"The Role of Gut Microbiota (Commensal Bacteria) and the Mucosal Barrier in the Pathogenesis of Inflammatory and Autoimmune Diseases and Cancer: Contribution of Germ-Free and Gnotobiotic Animal Models of Human Diseases","volume":"8","author":"Tlaskalova-Hogenova","year":"2011","journal-title":"Cell Mol Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1007\/s12038-019-9925-z","article-title":"Vaginal Microbiota in Pregnancy: Role in Induction of Labor and Seeding the Neonate's Microbiota","volume":"44","author":"Kervinen","year":"2019","journal-title":"J Biosci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"750479","DOI":"10.1155\/2008\/750479","article-title":"The Human Vaginal Bacterial Biota and Bacterial Vaginosis","volume":"2008","author":"Srinivasan","year":"2008","journal-title":"Interdiscip Perspect Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-092611-150157","article-title":"Vaginal Microbiome: Rethinking Health and Disease","volume":"66","author":"Ma","year":"2012","journal-title":"Annu Rev Microbiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.019","article-title":"Cervicovaginal Bacteria are a Major Modulator of Host Inflammatory Responses in the Female Genital Tract","volume":"42","author":"Anahtar","year":"2015","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.molimm.2015.02.030","article-title":"The Complement System and Adverse Pregnancy Outcomes","volume":"67","author":"Regal","year":"2015","journal-title":"Mol Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00378","article-title":"The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction","volume":"11","author":"Al-Nasiry","year":"2020","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923","article-title":"Complement: A Key System for Immune Surveillance and Homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"11520","DOI":"10.1007\/s00109-009-0572-y","article-title":"Complement Inhibition by Gram-Positive Pathogens: Molecular Mechanisms and Therapeutic Implications","volume":"88","author":"Laarman","year":"2010","journal-title":"J Mol Med (Berl)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1081\/IAS-120003658","article-title":"Validation of a High Sensitive Immunoenzymatic Assay to Establish the Origin of Immunoglobulins in Female Genital Secretions","volume":"23","author":"Bard","year":"2002","journal-title":"J Immunoas Immunochem"},{"key":"B11","doi-asserted-by":"publisher","first-page":"101337","DOI":"10.1016\/j.smim.2019.101337","article-title":"Regulation of the Complement System and Immunological Tolerance in Pregnancy","volume":"45","author":"Teiril\u00e4","year":"2019","journal-title":"Semin Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"101331","DOI":"10.1016\/j.smim.2019.101331","article-title":"Complement Dysregulation in Glomerulonephritis","volume":"45","author":"Kaartinen","year":"2019","journal-title":"Semin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.831044","article-title":"Editorial: Function and Dysfunction of Complement Factor H","volume":"12","author":"Jozsi","year":"2021","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2418-4","article-title":"Complement Factor H in Host Defense and Immune Evasion","volume":"74","author":"Parente","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12284","article-title":"Self-Nonself Discrimination by the Complement System","volume":"590","author":"Meri","year":"2016","journal-title":"FEBS Letter"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.563073","article-title":"Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery","volume":"11","author":"Livson","year":"2020","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00312","article-title":"Complement Activation and Regulation in Preeclamptic Placenta","volume":"5","author":"Lokki","year":"2014","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00589","article-title":"Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia","volume":"8","author":"Lokki","year":"2017","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.molimm.2020.03.021","article-title":"Dysregulation of Complement System During Pregnancy in Patients With Preeclampsia: A Prospective Study","volume":"122","author":"He","year":"2020","journal-title":"Mol Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1053\/j.ackd.2020.01.002","article-title":"Complement-Mediated Disorders in Pregnancy","volume":"27","author":"Amari Chinchilla","year":"2020","journal-title":"Adv Chronic Kidney Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1160\/TH11-08-0554","article-title":"Complement Activation in Patients With Isolated Antiphospholipid Antibodies or Primary Antiphospholipid Syndrome","volume":"107","author":"Breen","year":"2012","journal-title":"Thromb Haemostas"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2012.02.035","article-title":"Prepregnancy Obesity and Complement System Activation in Early Pregnancy and the Subsequent Development of Preeclampsia","volume":"206","author":"Lynch","year":"2012","journal-title":"Am J Obstet Gynecol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1097\/AOG.0b013e3181fc3afa","article-title":"Early Elevations of the Complement Activation Fragment C3a and Adverse Pregnancy Outcomes","volume":"117","author":"Lynch","year":"2011","journal-title":"Obstetr Gynecol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2015.11.001","article-title":"The Relationship of Circulating Proteins in Early Pregnancy With Preterm Birth","volume":"214","author":"Lynch","year":"2016","journal-title":"Am J Obstet Gynecol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2012.07.008","article-title":"Comparison of the Mechanisms Responsible for Cervical Remodeling in Preterm and Term Labor","volume":"97","author":"Gonzalez","year":"2013","journal-title":"J Reprod Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1177\/1099800416687648","article-title":"The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth","volume":"19","author":"Dunn","year":"2017","journal-title":"Biol Res Nurs"},{"key":"B27","doi-asserted-by":"publisher","first-page":"8988","DOI":"10.1038\/srep08988","article-title":"The Vaginal Microbiome During Pregnancy and the Postpartum Period in a European Population","volume":"5","author":"MacIntyre","year":"2015","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200010000-00035","article-title":"Complement C3 Cleavage and Cytokines Interleukin1beta and Tumor Necrosis Factor-Alpha in Otitis Media With Effusion","volume":"110","author":"N\u00e4rki\u00f6-M\u00e4kel\u00e4","year":"2000","journal-title":"Laryngosc"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.01.006","article-title":"Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma","volume":"187","author":"Riihil\u00e4","year":"2017","journal-title":"Am J Pathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: High Resolution Sample Inference From Illumina Amplicon Data","volume":"13","author":"Callahan","year":"2016","journal-title":"Nat Methods"},{"key":"B31","doi-asserted-by":"publisher","first-page":"100051","DOI":"10.1016\/j.humic.2018.11.002","article-title":"Exhaustive Repertoire of Human Vaginal Microbiota","volume":"11","author":"Khoudia Diop","year":"2019","journal-title":"Hum Microbio J"},{"key":"B32","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1002\/j.1538-7305.1948.tb01338.x","article-title":"A Mathematical Theory of Communication","volume":"27","author":"Shannon","year":"1948","journal-title":"Bell Syst Tech J"},{"key":"B33","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc (Methodological)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181477","article-title":"Comparative Analysis of Vaginal Microbiota Sampling Using 16S rRNA Gene Analysis","volume":"12","author":"Virtanen","year":"2017","journal-title":"PLoS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002611107","article-title":"Vaginal Microbiome of Reproductive-Age Women","author":"Ravel","year":"2011","journal-title":"Proc Natl Acad Sci Unit States America"},{"key":"B36","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/s41422-020-0332-7","article-title":"Interaction Between Microbiota and Immunity in Health and Disease","volume":"30","author":"Zheng","year":"2020","journal-title":"Cell Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-26-7-751","article-title":"Placental Estrogen Biosynthesis During Human Pregnancy","volume":"26","author":"Siiteri","year":"1966","journal-title":"J Clin Endocrinol Metab"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/2049-2618-2-10","article-title":"The Composition and Stability of the Vaginal Microbiota of Normal Pregnant Women is Different From That of non-Pregnant Women","volume":"2","author":"Romero","year":"2014","journal-title":"Microbiome"},{"key":"B39","doi-asserted-by":"publisher","first-page":"17558","DOI":"10.1038\/s41598-017-17972-0","article-title":"Diversity of Vaginal Microbiota Increases by the Time of Labor Onset","volume":"7","author":"Avershina","year":"2017","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2011.01.005","article-title":"Innate and Adaptive Immunity at Mucosal Surfaces of the Female Reproductive Tract: Stratification and Integration of Immune Protection Against the Transmission of Sexually Transmitted Infections","volume":"88","author":"Hickey","year":"2011","journal-title":"J Reprod Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00460-13","article-title":"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","volume":"4","author":"Witkin","year":"2013","journal-title":"mBio"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I - Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2011.07.016","article-title":"The New Face of Anaphylatoxins in Immune Regulation","volume":"217","author":"Zhou","year":"2012","journal-title":"Immunobiology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181292","article-title":"Genotypic and Phenotypic Diversity of Lactobacillus Rhamnosus Clinical Isolates, Their Comparison With Strain GG and Their Recognition by Complement System","volume":"12","author":"Nissil\u00e4","year":"2017","journal-title":"PLoS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"7750","DOI":"10.1038\/s41598-019-44157-8","article-title":"Vaginal Microbiota Composition Correlates Between Pap Smear Microscopy and Next Generation Sequencing and Associates to Socioeconomic Status","volume":"9","author":"Virtanen","year":"2019","journal-title":"Sci Rep"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.117.001731","article-title":"Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis","volume":"10","author":"Salminen","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.151.3.501","article-title":"Biosynthesis of the Complement Components and the Regulatory Proteins of the Alternative Complement Pathway by Human Peripheral Blood Monocytes","volume":"151","author":"Whaley","year":"1980","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.resmic.2017.09.003","article-title":"Lactobacillus Iners, the Unusual Suspect","volume":"168","author":"Vaneechoutte","year":"2017","journal-title":"Res Microbiol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00404-019-05142-8","article-title":"An Update on the Role of Atopobium Vaginae in Bacterial Vaginosis: What to Consider When Choosing a Treatment? A Mini Review","volume":"300","author":"Mendling","year":"2019","journal-title":"Arch Gynecol Obstet"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00541","article-title":"Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase From the Gram-Positive Bacterial Pathogen A. Vaginae, an Immunoevasive Factor That Interacts With the Human C5a Anaphylatoxin","volume":"8","author":"Querol-Garcia","year":"2017","journal-title":"Front Microbiol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"31118","DOI":"10.4049\/jimmunol.172.5.3111","article-title":"The Group B Streptococcal Beta and Pneumococcal Hic Proteins are Structurally Related Immune Evasion Molecules That Bind the Complement Inhibitor Factor H in an Analogous Fashion","volume":"172","author":"Jarva","year":"2004","journal-title":"J Immunol"},{"key":"B52","author":"Vuori E","year":"2018"},{"key":"B53","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1186\/s12884-020-03106-4","article-title":"Maternal Childbirth Experience in Induced and Spontaneous Labour Measured in a Visual Analog Scale and the Factors Influencing it; a Two-Year Cohort Study","volume":"20","author":"Adler","year":"2020","journal-title":"BMC Pregnan Childbirt"},{"key":"B54","doi-asserted-by":"publisher","first-page":"l344","DOI":"10.1136\/bmj.l344","article-title":"Induction of Labour at 41 Weeks Versus Expectant Management Until 42 Weeks (INDEX): Multicentre, Randomised non-Inferiority Trial","volume":"364","author":"Keulen","year":"2019","journal-title":"BMJ"},{"key":"B55","doi-asserted-by":"publisher","first-page":"104107","DOI":"10.1016\/j.ebiom.2022.104107","article-title":"Parity and Gestational Age are Associated With Vaginal Microbiota Composition in Term and Late Term Pregnancies","volume":"81","author":"Kervinen K","year":"2022","journal-title":"eBiomedicine"},{"key":"B56","author":"Kiuru","year":"2020"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.925630\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T12:56:09Z","timestamp":1658753769000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.925630\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":56,"alternative-id":["10.3389\/fimmu.2022.925630"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.925630","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]},"article-number":"925630"}}