Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models

Sydney Morrill, Nicole M Gilbert, Amanda L Lewis, Sydney Morrill, Nicole M Gilbert, Amanda L Lewis

Abstract

Koch's postulates dictate the use of experimental models to illustrate features of human disease and provide evidence for a singular organism as the cause. The underlying cause(s) of bacterial vaginosis (BV) has been debated in the literature for over half a century. In 1955, it was first reported that a bacterium now known as Gardnerella vaginalis may be the cause of a condition (BV) resulting in higher vaginal pH, thin discharge, a fishy odor, and the presence of epithelial cells covered in bacteria. Here we review contemporary and historical studies on BV with a focus on reports of experimental infections in human or animal models using Gardnerella vaginalis. We evaluate experimental evidence for the hypothesis that G. vaginalis is sufficient to trigger clinical features of BV or relevant health complications associated with the condition. Additionally, we evaluate in vivo models of co-infection employing G. vaginalis together with other bacterial species to investigate evidence for the hypothesis that G. vaginalis may encourage colonization or virulence of other potential pathogens. Together, these studies paint a complex picture in which G. vaginalis has both direct and indirect roles in the features, health complications, and co-infections associated with BV. We briefly review the current taxonomic landscape and genetic diversity pertinent to Gardnerella and note the limitations of sequence-based studies using different marker genes and priming sites. Although much more study is needed to refine our understanding of how BV develops and persists within the human host, applications of the experimental aspects of Koch's postulates have provided an important glimpse into some of the causal relationships that may govern this condition in vivo.

Keywords: Gardnerella vaginalis; animal model; bacterial vaginosis; co-infection; dysbiosis.

Copyright © 2020 Morrill, Gilbert and Lewis.

Figures

Figure 1
Figure 1
Gardnerella vaginalis (maroon) associated with the surface of a mouse vaginal epithelial cell (purple). Epithelial cells were collected from estrogenized mice by vaginal lavage with phosphate buffered saline. Epithelial cells were centrifuged, washed three times to remove endogenous bacteria then incubated for 4 h at 37°C ex vivo with G. vaginalis strain JCP8151B. Uranyl acetate staining was followed by transmission electron microscopy. Photo credit: Wandy Beatty. This image illustrates how the use of a small animal model can provide new resolution to aspects of BV that we appreciate, but do not fully understand. The pictured interaction provides evidence that in mice, as in women, G. vaginalis has an affinity with the vaginal epithelium. More broadly, it also supports the use of mouse models in reflecting at least some of the physiology we believe to occur in women.
Figure 2
Figure 2
Data from Criswell et al. (1969) plotted and analyzed to evaluate statistical difference between ability of 12 h vs. 24 h G. vaginalis cultures to cause signs of BV when inoculated into women.

References

    1. Ádám A., Pál Z., Terhes G., Szucs M., Gabay I. D., Urbán E. (2018). Culture- and PCR-based detection of BV associated microbiological profile of the removed IUDs and correlation with the time period of IUD in place and the presence of the symptoms of genital tract infection. Ann. Clin. Microbiol. Antimicrob 17:40. 10.1186/s12941-018-0293-6
    1. Agostini A., Beerli M., Franchi F., Bretelle F., Blanc B. (2003). Garnerella vaginalis bacteremia after vaginal myomectomy. Eur. J. Obstet. Gynecol. Reprod. Biol. 108:229. 10.1016/S0301-2115(02)00432-3
    1. Ahmed A., Earl J., Retchless A., Hillier S. L., Rabe L. K., Cherpes T. L., et al. (2012). Comparative genomic analyses of seventeen clinical isolates of Gardnerella vaginalis provides evidence of multiple genetically isolated clades consistent with sub-speciation into genovars. J. Bacteriol. 194:3922–37. 10.1128/JB.00056-12
    1. Akgul Y., Word R. A., Ensign L. M., Yamaguchi Y., Lydon J., Hanes J., et al. . (2014). Hyaluronan in cervical epithelia protects against infection-mediated preterm birth. J. Clin. Invest. 124, 5481–9. 10.1172/JCI78765
    1. Amatya R., Mandal P., Tuladhar H., Karki B. (2013). Urinary tract infection in vaginitis: a condition often overlooked. Nepal Med. Coll. J. 15, 65–7.
    1. Amegashie C. P., Gilbert N. M., Peipert J. F., Allsworth J. E., Lewis W. G., Lewis A. L. (2017). Relationship between nugent score and vaginal epithelial exfoliation. PLoS ONE 12:e0177797. 10.1371/journal.pone.0177797
    1. Amsel R., Totten P. A., Spiegel C. A., Chen K. C., Eschenbach D., Holmes K. K. (1983). Nonspecific vaginitis diagnostic criteria and microbial and epidemiologic associations. Am. J. Med. 74, 14–22. 10.1016/0002-9343(83)91112-9
    1. Anahtar M. N., Byrne E. H., Doherty K. E., Bowman B. A., Yamamoto H. S., Soumillon M., et al. . (2015). Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 42, 965–976. 10.1016/j.immuni.2015.04.019
    1. Balashov S. V., Mordechai E., Adelson M. E., Gygax S. E. (2014). Identification, quantification and subtyping of Gardnerella vaginalis in noncultured clinical vaginal samples by quantitative PCR. J. Med. Microbiol. 63, 162–175. 10.1099/jmm.0.066407-0
    1. Berardi-Grassias L., Roy O., Berardi J. C., Furioli J. (1988). Neonatal meningitis due to Gardnerella vaginalis. Eur. J. Clin. Microbiol. Infect. Dis. 7, 406–407. 10.1007/BF01962348
    1. Boggess K. A., Watts D. H., Hillier S. L., Krohn M. A., Benedetti T. J., Eschenbach D. A. (1996). Bacteremia shortly after placental separation during cesarean delivery. Obstet. Gynecol. 87, 779–784. 10.1016/0029-7844(96)00037-3
    1. Boskey E. R., Cone R. A., Whaley K. J., Moench T. R. (2001). Origins of vaginal acidity: high d/l lactate ratio is consistent with bacteria being the primary source. Hum. Reprod. 16, 1809–1813. 10.1093/humrep/16.9.1809
    1. Boskey E. R., Telsch K. M., Whaley K. J., Moench T. R., Cone R. A. (1999). Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect. Immun. 67, 5170–5175. 10.1128/IAI.67.10.5170-5175.1999
    1. Bradshaw C. S., Brotman R. M. (2015). Making inroads into improving treatment of bacterial vaginosis - striving for long-term cure. BMC Infect. Dis. 15:292. 10.1186/s12879-015-1027-4
    1. Bradshaw C. S., Morton A. N., Garland S. M., Horvath L. B., Kuzevska I., Fairley C. K. (2005). Evaluation of a point-of-care test, BVBlue, and clinical and laboratory criteria for diagnosis of bacterial vaginosis. J. Clin. Microbiol. 43, 1304–1308. 10.1128/JCM.43.3.1304-1308.2005
    1. Bradshaw C. S., Walker S. M., Vodstrcil L. A., Bilardi J. E., Law M., Hocking J. S., et al. . (2014). The influence of behaviors and relationships on the vaginal microbiota of women and their female partners: the WOW Health Study. J. Infect. Dis. 209, 1562–1572. 10.1093/infdis/jit664
    1. Briselden A. M., Hillier S. L. (1990). Longitudinal study of the biotypes of Gardnerella vaginalis. J. Clin. Microbiol. 28, 2761–2764. 10.1128/JCM.28.12.2761-2764.1990
    1. Briselden A. M., Moncla B. J., Stevens C. E., Hillier S. L. (1992). Sialidases (neuraminidases) in bacterial vaginosis and bacterial vaginosis-associated microflora. J. Clin. Microbiol. 30, 663–666. 10.1128/JCM.30.3.663-666.1992
    1. Brotman R. M., Klebanoff M. A., Nansel T. R., Yu K. F., Andrews W. W., Zhang J., et al. . (2010). Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection. J. Infect. Dis. 202, 1907–1915. 10.1086/657320
    1. Brusselaers N., Shrestha S., van de Wijgert J., Verstraelen H. (2019). Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am. J. Obstet. Gynecol. 221, 9–18.e8. 10.1016/j.ajog.2018.12.011
    1. C.f.D.C.a. Prevention (2015). Sexually Transmitted Diseases Treatment Guidelines: Bacterial Vaginosis.
    1. Callahan B. J., DiGiulio D. B., D.Goltsman S. A., Sun C. L., Costello E. K., Jeganathan P., et al. . (2017). 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. 114, 9966–9971. 10.1073/pnas.1705899114
    1. Campos A. C., Murta E. F., Michelin M. A., Reis C. (2012). Evaluation of cytokines in endocervical secretion and vaginal pH from women with bacterial vaginosis or human papillomavirus. ISRN Obstet. Gynecol. 2012:342075 10.5402/2012/342075
    1. Catlin B. W. (1992). Gardnerella vaginalis: characteristics, clinical considerations, and controversies. Clin. Microbiol. Rev. 5, 213–237. 10.1128/CMR.5.3.213
    1. Cauci S., Culhane J. F., Di Santolo M., McCollum K. (2008). Among pregnant women with bacterial vaginosis, the hydrolytic enzymes sialidase and prolidase are positively associated with interleukin-1beta. Am. J. Obstet. Gynecol. 198, 132.e1–137. 10.1016/j.ajog.2007.05.035
    1. Cauci S., Driussi S., Guaschino S., Isola M., Quadrifoglio F. (2002). Correlation of local interleukin-1beta levels with specific IgA response against Gardnerella vaginalis cytolysin in women with bacterial vaginosis. Am. J. Reprod. Immunol. 47, 257–264. 10.1034/j.1600-0897.2002.01096.x
    1. Chappell C. A., Rohan L. C., Moncla B. J., Wang L., Meyn L. A., Bunge K., et al. . (2014). The effects of reproductive hormones on the physical properties of cervicovaginal fluid. Am. J. Obstet. Gynecol. 211, 226.e1-7. 10.1016/j.ajog.2014.03.041
    1. Chen K. C., Forsyth P. S., Buchanan T. M., Holmes K. K. (1979). Amine content of vaginal fluid from untreated and treated patients with nonspecific vaginitis. J. Clin. Invest. 63, 828–835. 10.1172/JCI109382
    1. Chen Y., Han X., Guo P., Huang H., Wu Z., Liao K. (2018). Bacteramia caused by Gardnerella Vaginalis in a cesarean section patient. Clin. Lab. 64, 379–382. 10.7754/Clin.Lab.2017.171035
    1. Cherpes T. L., Melan M. A., Kant J. A., Cosentino L. A., Meyn L. A., Hillier S. L. (2005). Genital tract shedding of herpes simplex virus type 2 in women: effects of hormonal contraception, bacterial vaginosis, and vaginal group B. Streptococcus colonization. Clin. Infect. Dis. 40, 1422–8. 10.1086/429622
    1. Couper K. N., Blount D. G., Riley E. M. (2008). IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777. 10.4049/jimmunol.180.9.5771
    1. Cox C., McKenna J. P., Watt A. P., Coyle P. V. (2015). New assay for Gardnerella vaginalis loads correlates with Nugent scores and has potential in the diagnosis of bacterial vaginosis. J. Med. Microbiol. 64, 978–984. 10.1099/jmm.0.000118
    1. Criswell B. S., Gardner H. L., Dukes C. D. (1969). Haemophilus vaginalis: vaginitis by inoculation from culture. Obstetr. Gynecol. 33, 195–199.
    1. Di Paola M., Sani C., Clemente A. M., Iossa A., Perissi E., Castronovo G., et al. . (2017). Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection. Sci. Rep. 7:10200. 10.1038/s41598-017-09842-6
    1. DiGiulio D. B. (2012). Diversity of microbes in amniotic fluid. Sem. Fetal Neonatal. Med. 17, 2–11. 10.1016/j.siny.2011.10.001
    1. DiGiulio D. B., Romero R., Kusanovic J. P., Gomez R., Kim C. J., Seok K. S., et al. . (2010). Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am. J. Reprod. Immunol. 64, 38–57. 10.1111/j.1600-0897.2010.00830.x
    1. Donders G. G., Vereecken A., Bosmans E., Dekeersmaecker A., Salembier G., Spitz B. (2002). Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. BJOG 109, 34–43. 10.1111/j.1471-0528.2002.00432.x
    1. Duell B. L., Su Y. C., Riesbeck K. (2016). Host-pathogen interactions of nontypeable Haemophilus influenzae: from commensal to pathogen. FEBS Lett. 590, 3840–3853. 10.1002/1873-3468.12351
    1. Dworkin M., Falkow S., Rosenberg E., Schleifer K.-H., Stackebrandt E. (2006). The Prokaryotes Vol 3: Archaea. Bacteria: Firmicutes, Actinomycetes Springer-Verlag New York; 10.1007/0-387-30744-3
    1. Evans A. S. (1976). Causation and disease: the Henle-Koch postulates revisited. Yale J. Biol. Med. 49, 175–195.
    1. Fairley K. F., Birch D. F. (1983). Unconventional bacteria in urinary tract disease: Gardnerella vaginalis. Kidney Int. 23, 862–865. 10.1038/ki.1983.107
    1. Fettweis J. M., Serrano M. G., Brooks J. P., Edwards D. J., Girerd P. H., Parikh H. I., et al. . (2019). The vaginal microbiome and preterm birth. Nat. Med. 25, 1012–1021. 10.1038/s41591-019-0450-2
    1. Fidel P. I., Romero R., Jr, Maymon E., Hertelendy F. (1998). Bacteria-induced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations. J. Matern. Fetal Med. 7, 222–226. 10.3109/14767059809020447
    1. Field N. T., Newton E. R., Kagan-Hallet K., Peairs W. A. (1993). Perinatal effects of Gardnerella vaginalis deciduitis in the rabbit. Am. J. Obstet. Gynecol. 168, 988–994. 10.1016/S0002-9378(12)90858-3
    1. Forsum U., Holst E., Larsson P. G., Vasquez A., Jakobsson T., Mattsby-Baltzer I. (2005). Bacterial vaginosis–a microbiological and immunological enigma. APMIS 113, 81–90. 10.1111/j.1600-0463.2005.apm1130201.x
    1. Forsum U., Larsson P. G., Spiegel C. (2008). Scoring vaginal fluid smears for diagnosis of bacterial vaginosis: need for quality specifications. APMIS 116, 156–159. 10.1111/j.1600-0463.2008.00984.x
    1. Fredricks D. N., Relman D. A. (1996). Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates. Clin. Microbiol. Rev. 9, 18–33. 10.1128/CMR.9.1.18
    1. Gardner H. L., Dukes C. D. (1954). New etiologic agent in nonspecific bacterial vaginitis. Science 120, 853–853. 10.1126/science.120.3125.853
    1. Gardner H. L., Dukes C. D. (1955). Haemophilus vaginalis vaginitis: a newly defined specific infection previously classified non-specific vaginitis. Am. J. Obstetr. Gynecol. 69, 962–976. 10.1016/0002-9378(55)90095-8
    1. Gardner H. L., Dukes C. D. (1959). Hemophilus vaginalis vaginitis. Ann. N.Y. Acad. Sci. 83, 280–289. 10.1111/j.1749-6632.1960.tb40901.x
    1. Gautam R., Borgdorff H., Jespers V., Francis S. C., Verhelst R., Mwaura M., et al. . (2015). Correlates of the molecular vaginal microbiota composition of African women. BMC Infect. Dis. 15:86. 10.1186/s12879-015-0831-1
    1. Gelber S. E., Aguilar J. L., Lewis K. L., Ratner A. J. (2008). Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis. J. Bacteriol. 190, 3896–903. 10.1128/JB.01965-07
    1. Gibbs R. S. (1993). Chorioamnionitis and bacterial vaginosis. Am. J. Obstet. Gynecol. 169, 460–462. 10.1016/0002-9378(93)90341-F
    1. Gibbs R. S., McDuffie R. S, Jr, Kunze M., Barr J. M., Wolf D. M., Sze C. I., et al. . (2004). Experimental intrauterine infection with Prevotella bivia in New Zealand White rabbits. Am. J. Obstet. Gynecol. 190, 1082–1086. 10.1016/j.ajog.2003.10.700
    1. Gilbert N. M., Lewis W. G., Lewis A. L. (2013). Clinical features of bacterial vaginosis in a murine model of vaginal infection with Gardnerella vaginalis. PLoS ONE 8:e59539. 10.1371/journal.pone.0059539
    1. Gilbert N. M., Lewis W. G., Li G., Sojka D. K., Lubin J. B., Lewis A. L. (2019). Gardnerella vaginalis and prevotella bivia trigger distinct and overlapping phenotypes in a mouse model of bacterial vaginosis. J. Infect. Dis. 220, 1099–1108. 10.1093/infdis/jiy704
    1. Gilbert N. M., O'Brien V. P., Lewis A. L. (2017). Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog. 13:e1006238. 10.1371/journal.ppat.1006238
    1. Giraldo P. C., de Carvalho J. B., do Amaral R. L., da Silveira Goncalves A.K., Eleuterio J, Jr, Guimaraes F. (2012). Identification of immune cells by flow cytometry in vaginal lavages from women with vulvovaginitis and normal microflora. Am. J. Reprod. Immunol. 67, 198–205. 10.1111/j.1600-0897.2011.01093.x
    1. Goldenberg R. L., Klebanoff M. A., Nugent R., Krohn M. A., Hillier S., Andrews W. W. (1996). Bacterial colonization of the vagina during pregnancy in four ethnic groups. Vaginal Infections and Prematurity Study Group. Am. J. Obstet. Gynecol. 174, 1618–1621. 10.1016/S0002-9378(96)70617-8
    1. Goltsman S. A., Sun C. L., Proctor D. M., DiGiulio D. B., Robaczewska A., Thomas B. C., et al. . (2018). Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome. Genome Res. 28, 1467–1480. 10.1101/gr.236000.118
    1. Gosmann C., Anahtar M. N., Handley S. A., Farcasanu M., Abu-Ali G., Bowman B. A., et al. . (2017). Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity 46, 29–37. 10.1016/j.immuni.2016.12.013
    1. Gottschick C., Deng Z.-L., Vital M., Masur C., Abels C., Pieper D. H., et al. . (2017). The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome 5:99. 10.1186/s40168-017-0305-3
    1. Graspeuntner S., Loeper N., Künzel S., Baines J. F., Rupp J. (2018). Selection of validated hypervariable regions is crucial in 16S-based microbiota studies of the female genital tract. Sci. Rep. 8:9678. 10.1038/s41598-018-27757-8
    1. Greenwood J. R., Pickett M. J. (1980). Transfer of haemophilus vaginalis gardner and dukes to a new genus, Gardnerella: G. vaginalis (Gardner and Dukes) comb. nov. Int. J. Syst. Bacteriol. 30, 170–178. 10.1099/00207713-30-1-170
    1. Harmanli O. H., Cheng G. Y., Nyirjesy P., Chatwani A., Gaughan J. P. (2000). Urinary tract infections in women with bacterial vaginosis. Obstetr. Gynecol. 95, 710–712. 10.1097/00006250-200005000-00015
    1. Hemalatha R., Ramalaxmi B. A., KrishnaSwetha G., Kumar P. U., Rao D. M., Balakrishna N., et al. . (2012). Cervicovaginal inflammatory cytokines and sphingomyelinase in women with and without bacterial vaginosis. Am. J. Med. Sci. 344, 35–39. 10.1097/MAJ.0b013e318235597b
    1. Herbst-Kralovetz M. M., Pyles R. B., Ratner A. J., Sycuro L. K., Mitchell C. (2016). New systems for studying intercellular interactions in bacterial vaginosis. J. Infect. Dis. 214, S6–S13. 10.1093/infdis/jiw130
    1. Hickey R. J., Forney L. J. (2014). Gardnerella vaginalis does not always cause bacterial vaginosis. J. Infect. Dis. 210, 1682–1683. 10.1093/infdis/jiu303
    1. Hilbert D. W., Schuyler J. A., Adelson M. E., Mordechai E., Sobel J. D., Gygax S. E. (2017). Gardnerella vaginalis population dynamics in bacterial vaginosis. Eur. J. Clin. Microbiol. Infect. Dis. 36, 1269–1278. 10.1007/s10096-017-2933-8
    1. Hill G. B. (1998). Preterm birth: associations with genital and possibly oral microflora. Ann. Periodontol. 3, 222–32. 10.1902/annals.1998.3.1.222
    1. Hill J. E., Albert A. Y. K., VOGUE Research Group . (2019). Resolution and Cooccurrence Patterns of Gardnerella leopoldii, G. swidsinskii, G. piotii, and G. vaginalis within the Vaginal Microbiome. Infect. Immun 87:e00532–19. 10.1128/IAI.00532-19
    1. Hillebrand L., Harmanli O. H., Whiteman V., Khandelwal M. (2002). Urinary tract infections in pregnant women with bacterial vaginosis. Am. J. Obstet. Gynecol. 186, 916–917. 10.1067/mob.2002.123987
    1. Hillier S. L. (1993). Diagnostic microbiology of bacterial vaginosis. Am. J. Obstet. Gynecol. 169, 455–459. 10.1016/0002-9378(93)90340-O
    1. Hillier S. L., Krohn M. A., Rabe L. K., Klebanoff S. J., Eschenbach D. A. (1993). The normal vaginal flora, H2O2-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin. Infect. Dis. 16 (Suppl. 4), S273–S281. 10.1093/clinids/16.Supplement_4.S273
    1. Hillier S. L., Martius J., Krohn M., Kiviat N., Holmes K. K., Eschenbach D. A. (1988). A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N. Engl. J. Med. 319, 972–978. 10.1056/NEJM198810133191503
    1. Hitti J., Hillier S. L., Agnew K. J., Krohn M. A., Reisner D. P., Eschenbach D. A. (2001). Vaginal indicators of amniotic fluid infection in preterm labor. Obstet. Gynecol. 97, 211–219. 10.1097/00006250-200102000-00010
    1. Hymes S. R., Randis T. M., Sun T. Y., Ratner A. J. (2013). DNase Inhibits Gardnerella vaginalis biofilms in vitro and in vivo. J. Infect. Dis. 207, 1491–1497. 10.1093/infdis/jit047
    1. Jang S. E., Jeong J. J., Choi S. Y., Kim H., Han M. J., Kim D. H. (2017). Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus La-14 Attenuate Gardnerella vaginalis-infected bacterial vaginosis in mice. Nutrients 9:531 10.3390/nu9060531
    1. Janulaitiene M., Gegzna V., Baranauskiene L., Bulavaite A., Simanavicius M., Pleckaityte M. (2018). Phenotypic characterization of Gardnerella vaginalis subgroups suggests differences in their virulence potential. PLoS ONE 13:e0200625. 10.1371/journal.pone.0200625
    1. Jarrett O. D., Srinivasan S., Richardson B. A., Fiedler T., Wallis J. M., Kinuthia J., et al. . (2019). Specific vaginal bacteria are associated with an increased risk of trichomonas vaginalis acquisition in women. J. Infect. Dis. 220, 1503–1510. 10.1093/infdis/jiz354
    1. Jerse A. E., Wu H., Packiam M., Vonck R. A., Begum A. A., Garvin L. E. (2011). Estradiol-treated female mice as surrogate hosts for neisseria gonorrhoeae genital tract infections. Front. Microbiol. 2:107. 10.3389/fmicb.2011.00107
    1. Johnson A. P., Hetherington C. M., Osborn M. F., Southerton G., London W. T., Easmon C. S. F., et al. . (1984). A study of the susceptibility of three species of primate to vaginal colonization with Gardnerella vaginalis. Br. J. Exp. Pathol. 65, 389–396.
    1. Joo H.-M., Hyun Y. J., Myoung K.-S., Ahn Y. T., Lee J.-H., Huh C. S., et al. . (2011). Lactobacillus johnsonii HY7042 ameliorates Gardnerella vaginalis-induced vaginosis by killing Gardnerella vaginalis and inhibiting NF-κB activation. Int. Immunopharmacol. 11, 1758–1765. 10.1016/j.intimp.2011.07.002
    1. Josephson S., Sturino K., Zabransky R., Williams J. (1988b). Gardnerella vaginalis in he urinary tract. Obst. Gynecol. 71, 245–250.
    1. Josephson S., Thomason J., Sturino K., Zabransky R., Williams J. (1988a). Gardnerella vaginalis in the urinary tract: incidence and significance in a hospital population. Obstetr. Gynecol. 71, 245–250.
    1. Kajikawa S., Kaga N., Futamura Y., Kakinuma C., Shibutani Y. (1998). Lipoteichoic acid induces preterm delivery in mice. J. Pharmacol. Toxicol. Methods 39, 147–154. 10.1016/S1056-8719(98)00015-X
    1. Kim D. E., Kim J. K., Han S. K., Jang S. E., Han M. J., Kim D. H. (2019). Lactobacillus plantarum NK3 and bifidobacterium longum NK49 alleviate bacterial vaginosis and osteoporosis in mice by suppressing NF-kappaB-Linked TNF-alpha expression. J. Med. Food 22, 1022–1031. 10.1089/jmf.2019.4419
    1. Kline K. A., Lewis A. L. (2016). Gram-positive uropathogens, polymicrobial urinary tract infection the emerging microbiota of the urinary tract. Microbiol. Spectr. 4. 10.1128/microbiolspec.UTI-0012-2012
    1. Kramer H., Kuffel G., Thomas-White K., Wolfe A. J., Vellanki K., Leehey D. J., et al. . (2018). Diversity of the midstream urine microbiome in adults with chronic kidney disease. Int. Urol. Nephrol. 50, 1123–1130. 10.1007/s11255-018-1860-7
    1. Krismer B., Weidenmaier C., Zipperer A., Peschel A. (2017). The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota. Nat. Rev. Microbiol. 15, 675–687. 10.1038/nrmicro.2017.104
    1. Krohn M. A., Hillier S. L., Lee M. L., Rabe L. K., Eschenbach D. A. (1991). Vaginal bacteroides species are associated with an increased rate of preterm delivery among women in preterm labor. J. Infect. Dis. 164, 88–93. 10.1093/infdis/164.1.88
    1. Laniewski P., Barnes D., Goulder A., Cui H., Roe D. J., Chase D. M., et al. . (2018). Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci. Rep. 8:7593. 10.1038/s41598-018-25879-7
    1. Lennard K., Dabee S., Barnabas S. L., Havyarimana E., Blakney A., Jaumdally S. Z., et al. . (2017). Microbial composition predicts genital tract inflammation and persistent bacterial vaginosis in south african adolescent females. Infect. Immun. 86, e00410–17. 10.1128/IAI.00410-17
    1. Leopold S. (1953). Heretofore undescribed organism isolated from the genitourinary system. U.S. Armed Forces Med. J. 4, 263–266.
    1. Lev-Sagie A., Goldman-Wohl D., Cohen Y., Dori-Bachash M., Leshem A., Mor U., et al. . (2019). Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat. Med. 25, 1500–1504. 10.1038/s41591-019-0600-6
    1. Lewis W. G., Robinson L. S., Gilbert N. M., Perry J. C., Lewis A. L. (2013). Degradation, foraging, and depletion of mucus sialoglycans by the vagina-adaptedactinobacterium Gardnerella vaginalis. J. Biol. Chem. 288, 12067–12079. 10.1074/jbc.M113.453654
    1. Mårdh P. A., Møller B. R. (1984). The grivet monkey as a model for study of vaginitis. Challenge with anaerobic curved rods and Gardnerella vaginalis. Scand. J. Urol. Nephrol. Suppl. 86, 201–205.
    1. Malki K., Shapiro J. W., Price T. K., Hilt E. E., Thomas-White K., Sircar T., et al. . (2016). Genomes of gardnerella strains reveal an abundance of prophages within the bladder microbiome. PLoS ONE 11:e0166757. 10.1371/journal.pone.0166757
    1. Mason M. J., Winter A. J. (2017). How to diagnose and treat aerobic and desquamative inflammatory vaginitis. Sex. Transm. Infect. 93, 8–10. 10.1136/sextrans-2015-052406
    1. Masson L., Barnabas S., Deese J., Lennard K., Dabee S., Gamieldien H., et al. . (2019). Inflammatory cytokine biomarkers of asymptomatic sexually transmitted infections and vaginal dysbiosis: a multicentre validation study. Sex. Transm. Infect. 95, 5–12. 10.1136/sextrans-2017-053506
    1. McDuffie R. S., Kunze M., Barr J., Wolf D., Sze C.-I., Shikes R., et al. . (2002). Chronic intrauterine and fetal infection with Gardnerella vaginalis. Am. J. Obstet. Gynecol. 187, 1263–1266. 10.1067/mob.2002.127129
    1. McGregor J. A., French J. I., Jones W., Milligan K., McKinney P. J., Patterson E., et al. . (1994). Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am. J. Obstet. Gynecol. 170, 1048–1059; discussion 1059-60. 10.1016/S0002-9378(94)70098-2
    1. Mendling W., Weissenbacher E. R., Gerber S., Prasauskas V., Grob P. (2016). Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review. Arch. Gynecol. Obstet. 293, 469–84. 10.1007/s00404-015-3914-8
    1. Miller E. A., Beasley D. E., Dunn R. R., Archie E. A. (2016). Lactobacilli dominance and vaginal pH: why is the human vaginal microbiome unique? Front. Microbiol. 7:1936. 10.3389/fmicb.2016.01936
    1. Miller E. A., Livermore J. A., Alberts S. C., Tung J., Archie E. A. (2017). Ovarian cycling and reproductive state shape the vaginal microbiota in wild baboons. Microbiome 5:8. 10.1186/s40168-017-0228-z
    1. Mitchell C., Marrazzo J. (2014). Bacterial vaginosis and the cervicovaginal immune response. Am. J. Reprod. Immunol. 71, 555–563. 10.1111/aji.12264
    1. Monif G. R., Baer H. (1976). Polymicrobial bacteremia in obstetric patients. Obstet. Gynecol 48, 167–169.
    1. Muzny C. A., Lensing S. Y., Aaron K. J., Schwebke J. R. (2019b). Incubation period and risk factors support sexual transmission of bacterial vaginosis in women who have sex with women. Sex. Transm. Infect. 95, 511–515. 10.1136/sextrans-2018-053824
    1. Muzny C. A., Taylor C. M., Swords W. E., Tamhane A., Chattopadhyay D., Cerca N., et al. . (2019a). An updated conceptual model on the pathogenesis of bacterial vaginosis. J. Infect. Dis. 220, 1399–1405. 10.1093/infdis/jiz342
    1. Mysorekar I. U., Hultgren S. J. (2006). Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. PNAS 103, 14170–14175. 10.1073/pnas.0602136103
    1. Myziuk L., Romanowski B., Johnson S. C. (2003). BVBlue test for diagnosis of bacterial vaginosis. J. Clin. Microbiol. 41, 1925–198. 10.1128/JCM.41.5.1925-1928.2003
    1. Nelson T. M., Borgogna J.-L. C., Brotman R. M., Ravel J., Walk S. T., Yeoman C. J. (2015). Vaginal biogenic amines: biomarkers of bacterial vaginosis or precursors to vaginal dysbiosis? Front. Physiol. 6:253. 10.3389/fphys.2015.00253
    1. Nelson T. M., Borgogna J. C., Michalek R. D., Roberts D. W., Rath J. M., Glover E. D., et al. . (2018). Cigarette smoking is associated with an altered vaginal tract metabolomic profile. Sci. Rep. 8:852. 10.1038/s41598-017-14943-3
    1. Nugent R. P., Krohn M. A., Hillier S. L. (1991). Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J. Clin. Microbiol. 29, 297–301. 10.1128/JCM.29.2.297-301.1991
    1. Obiero J. A., Waititu K. K., Mulei I., Omar F. I., Jaoko W., Mwethera P. G. (2016). Baboon vaginal microbial flora. J. Med. Primatol. 45, 147–155. 10.1111/jmp.12217
    1. Olmsted S. S., Meyn L. A., Rohan L. C., Hillier S. L. (2003). Glycosidase and proteinase activity of anaerobic gram-negative bacteria isolated from women with bacterial vaginosis. Sex. Transm. Dis. 30, 257–61. 10.1097/00007435-200303000-00016
    1. Olson K. M., Boohaker L. J., Schwebke J. R., Aslibekyan S., Muzny C. A. (2018). Comparisons of vaginal flora patterns among sexual behaviour groups of women: implications for the pathogenesis of bacterial vaginosis. Sex. Health 15, 61–67. 10.1071/SH17087
    1. Pearce M. M., Hilt E. E., Rosenfeld A. B., Zilliox M. J., Thomas-White K., Fok C., et al. . (2014). The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio 5:e01283–14-e01283. 10.1128/mBio.01283-14
    1. Pearce M. M., Zilliox M. J., Rosenfeld A. B., Thomas-White K. J., Richter H. E., Nager C. W., et al. . (2015). The female urinary microbiome in urgency urinary incontinence. Am. J. Obstetr. Gynecol. 213, 347.e1–e11. 10.1016/j.ajog.2015.07.009
    1. Petrina M. A. B., Cosentino L. A., Wiesenfeld H. C., Darville T., Hillier S. L. (2019). Susceptibility of endometrial isolates recovered from women with clinical pelvic inflammatory disease or histological endometritis to antimicrobial agents. Anaerobe 56, 61–65. 10.1016/j.anaerobe.2019.02.005
    1. Piot P., van Dyck E., Goodfellow M., Falkow S. (1980). A taxonomic study of Gardnerella vaginalis (Haemophilus vaginalis) gardner and dukes 1955. J. Gen. Microbiol. 119, 373–396. 10.1099/00221287-119-2-373
    1. Piot P., Van Dyck E., Peeters M., Hale J., Totten P. A., Holmes K. K. (1984). Biotypes of Gardnerella vaginalis. J. Clin. Microbiol. 20, 677–679. 10.1128/JCM.20.4.677-679.1984
    1. Pleckaityte M., Janulaitiene M., Lasickiene R., Zvirbliene A. (2012). Genetic and biochemical diversity of Gardnerella vaginalis strains isolated from women with bacterial vaginosis. FEMS Immunol. Med. Microbiol. 65, 69–77. 10.1111/j.1574-695X.2012.00940.x
    1. Plummer E. L., Vodstrcil L. A., Murray G. L., Fairley C. K., Danielewski J. A., Garland S. M., et al. (2019). Gardnerella vaginalis clade distribution is associated with behavioural practices and Nugent Score in women who have sex with women. J. Infect. Dis. 221, 464–463. 10.1093/infdis/jiz474
    1. Pybus V., Onderdonk A. B. (1997). Evidence for a commensal, symbiotic relationship between Gardnerella vaginalis and prevotella bivia involving ammonia: potential significance for bacterial vaginosis. J. Infect. Dis. 175, 406–413. 10.1093/infdis/175.2.406
    1. Ralph S. G., Rutherford A. J., Wilson J. D. (1999). Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 319, 220–223. 10.1136/bmj.319.7204.220
    1. Ravel J., Gajer P., Abdo Z., Schneider G. M., S.Koenig S. K., McCulle S. L., et al. . (2011). Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. U. S. A. 108, 4680–4687. 10.1073/pnas.1002611107
    1. Reimer L. G., Reller L. B. (1984). Gardnerella vaginalis bacteremia: a review of thirty cases. Obstet. Gynecol 64, 170–172.
    1. Robinson L. S., Schwebke J., Lewis W. G., Lewis A. L. (2019). Identification and characterization of NanH2 and NanH3, the enzymes responsible for sialidase activity in the vaginal bacterium Gardnerella vaginalis. J. Biol. Chem. 118:00622 10.1074/jbc.RA118.006221
    1. Rosshart S. P., Vassallo B. G., Angeletti D., Hutchinson D. S., Morgan A. P., Takeda K., et al. . (2017). Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 171, 1015–1028.e13. 10.1016/j.cell.2017.09.016
    1. Schwebke J. R., Muzny C. A., Josey W. E. (2014a). Reply to hickey and forney. J. Infect. Dis. 210, 1683–1684. 10.1093/infdis/jiu304
    1. Schwebke J. R., Muzny C. A., Josey W. E. (2014b). Role of Gardnerella vaginalis in the pathogenesis of bacterial vaginosis: a conceptual model. J. Infect. Dis. 210, 338–343. 10.1093/infdis/jiu089
    1. Shabayek S., Spellerberg B. (2018). Group B streptococcal colonization, molecular characteristics, and epidemiology. Front. Microbiol. 9:437. 10.3389/fmicb.2018.00437
    1. Shannon B., Gajer P., Yi T. J., Ma B., Humphrys M. S., Thomas-Pavanel J., et al. . (2017). Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J. Infect. Dis. 215, 1366–1375. 10.1093/infdis/jix088
    1. Sharami S. H., Afrakhteh M., Shakiba M. (2007). Urinary tract infections in pregnant women with bacterial vaginosis. J. Obstet. Gynaecol. 27, 252–254. 10.1080/01443610701194846
    1. Sheiness D., Dix K., Watanabe S., Hillier S. L. (1992). High levels of Gardnerella vaginalis detected with an oligonucleotide probe combined with elevated pH as a diagnostic indicator of bacterial vaginosis. J. Clin. Microbiol. 30, 642–648. 10.1128/JCM.30.3.642-648.1992
    1. Shipitsyna E., Krysanova A., Khayrullina G., Shalepo K., Savicheva A., Guschin A., et al. . (2019). Quantitation of all four Gardnerella vaginalis clades detects abnormal vaginal microbiota characteristic of bacterial vaginosis more accurately than putative G. vaginalis sialidase A gene count. Mol. Diagn. Ther. 23, 139–147. 10.1007/s40291-019-00382-5
    1. Shipitsyna E., Roos A., Datcu R., Hallen A., Fredlund H., Jensen J. S., et al. . (2013). Composition of the vaginal microbiota in women of reproductive age–sensitive and specific molecular diagnosis of bacterial vaginosis is possible? PLoS ONE 8:e60670. 10.1371/journal.pone.0060670
    1. Sierra L.-J., Brown A. G., Barilá G. O., Anton L., Barnum C. E., Shetye S. S., et al. . (2018). Colonization of the cervicovaginal space with Gardnerella vaginalis leads to local inflammation and cervical remodeling in pregnant mice. PLoS ONE 13:e0191524. 10.1371/journal.pone.0191524
    1. Silver H. M., Sperling R. S., St Clair P. J., Gibbs R. S. (1989). Evidence relating bacterial vaginosis to intraamniotic infection. Am. J. Obstet. Gynecol. 161, 808–12. 10.1016/0002-9378(89)90406-7
    1. Spandorfer S., Neuer A., Paulo G., Rosenwaks Z., Witkin S. (2001). Relationship of abnormal vaginal flora, proinflammatory cytokines and idiopathic infertility in women undergoing IVF. J. Reprod. Med. 46, 806–10.
    1. Spear G. T., Gilbert D., Sikaroodi M., Doyle L., Green L., Gillevet P. M., et al. . (2010). Identification of rhesus macaque genital microbiota by 16S pyrosequencing shows similarities to human bacterial vaginosis: implications for use as an animal model for HIV vaginal infection. AIDS Res. Hum. Retroviruses 26, 193–200. 10.1089/aid.2009.0166
    1. Srinivasan S., Hoffman N. G., Morgan M. T., Matsen F. A., Fiedler T. L., Hall R. W., et al. . (2012). Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria. PLoS ONE 7:e37818. 10.1371/journal.pone.0037818
    1. Srinivasan S., Morgan M. T., Fiedler T. L., Djukovic D., Hoffman N. G., Raftery D., et al. . (2015). Metabolic signatures of bacterial vaginosis. MBio 6, e00204–15. 10.1128/mBio.00204-15
    1. Srinivasan S., Morgan M. T., Liu C., Matsen F. A., Hoffman N. G., Fiedler T. L., et al. . (2013). More than meets the eye: associations of vaginal bacteria with gram stain morphotypes using molecular phylogenetic analysis. PLoS ONE 8:e78633. 10.1371/journal.pone.0078633
    1. Stumpf R. M., Wilson B. A., Rivera A., Yildirim S., Yeoman C. J., Polk J. D., et al. . (2013). The primate vaginal microbiome: comparative context and implications for human health and disease. Am. J. Phys. Anthropol. 152, 119–134. 10.1002/ajpa.22395
    1. Sumati A. H., Saritha N. K. (2009). Association of urinary tract infection in women with bacterial vaginosis. J. Glob. Infect. Dis. 1, 151–152. 10.4103/0974-777X.56254
    1. Svare J. A., Schmidt H., Hansen B. B., Lose G. (2006). Bacterial vaginosis in a cohort of Danish pregnant women: prevalence and relationship with preterm delivery, low birthweight and perinatal infections. BJOG 113, 1419–1425. 10.1111/j.1471-0528.2006.01087.x
    1. Swidsinski A., Mendling W., Loening-Baucke V., Ladhoff A., Swidsinski S., Hale L. P., et al. . (2005). Adherent biofilms in bacterial vaginosis. Obstet. Gynecol. 106, 1013–1023. 10.1097/01.AOG.0000183594.45524.d2
    1. Swidsinski A., Mendling W., Loening-Baucke V., Swidsinski S., Dörffel Y., Scholze J., et al. . (2008). An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am. J. Obstetr. Gynecol. 198, 97.e1–97.e6. 10.1016/j.ajog.2007.06.039
    1. Teixeira G. S., Carvalho F. P., Arantes R. M., Nunes A. C., Moreira J. L., Mendonca M., et al. . (2012). Characteristics of Lactobacillus and Gardnerella vaginalis from women with or without bacterial vaginosis and their relationships in gnotobiotic mice. J. Med. Microbiol. 61, 1074–81. 10.1099/jmm.0.041962-0
    1. Thomas-White K. J., Hilt E. E., Fok C., Pearce M. M., Mueller E. R., Kliethermes S., et al. . (2016). Incontinence medication response relates to the female urinary microbiota. Int. Urogynecol. J. 27, 723–733. 10.1007/s00192-015-2847-x
    1. Timmons B., Akins M., Mahendroo M. (2010). Cervical remodeling during pregnancy and parturition. Trends Endocrinol. Metab. 21, 353–361. 10.1016/j.tem.2010.01.011
    1. Totten P. A., Amsel R., Hale J., Piot P., Holmes K. K. (1982). Selective differential human blood bilayer media for isolation of Gardnerella (Haemophilus) vaginalis. J. Clin. Microbiol. 15, 141–147. 10.1128/JCM.15.1.141-147.1982
    1. Trinh H. T., Lee I. A., Hyun Y. J., Kim D. H. (2011). Artemisia princeps Pamp. Essential oil and its constituents eucalyptol and alpha-terpineol ameliorate bacterial vaginosis and vulvovaginal candidiasis in mice by inhibiting bacterial growth and NF-kappaB activation. Planta Med. 77, 1996–2002. 10.1055/s-0031-1280094
    1. Turovskiy Y., Sutyak Noll K., Chikindas M. L. (2011). The aetiology of bacterial vaginosis. J. Appl. Microbiol. 110, 1105–28. 10.1111/j.1365-2672.2011.04977.x
    1. Uchihashi M., Bergin I. L., Bassis C. M., Hashway S. A., Chai D., Bell J. D. (2015). Influence of age, reproductive cycling status, and menstruation on the vaginal microbiome in baboons (Papio anubis). Am. J. Primatol. 77, 563–578. 10.1002/ajp.22378
    1. Van De Wijgert J. H. H. M. (2017). The vaginal microbiome and sexually transmitted infections are interlinked: consequences for treatment and prevention. PLoS Med. 14:E1002478. 10.1371/journal.pmed.1002478
    1. Vaneechoutte M., Guschin A., Van Simaey L., Gansemans Y., Van Nieuwerburgh F., Cools P. (2019). Emended description of Gardnerella vaginalis and description of Gardnerella leopoldii sp. nov., Gardnerella piotii sp. nov. and Gardnerella swidsinskii sp. nov., with delineation of 13 genomic species within the genus Gardnerella. Int. J. Syst. Evol. Microbiol. 69, 679–687. 10.1099/ijsem.0.003200
    1. Venkataramani T. K., Rathbun H. K. (1976). Corynebacterium vaginale (Hemophilus vaginalis) bacteremia: clinical study of 29 cases. Johns Hopkins Med. J. 139, 93–97.
    1. Watts D. H., Krohn M. A., Hillier S. L., Eschenbach D. A. (1990). Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet. Gynecol. 75, 52–58.
    1. Weiser J. N., Ferreira D. M., Paton J. C. (2018). Streptococcus pneumoniae: transmission, colonization and invasion. Nat. Rev. Microbiol. 16, 355–367. 10.1038/s41579-018-0001-8
    1. Wiesenfeld H. C., Hillier S. L., Krohn M. A., Landers D. V., Sweet R. L. (2003). Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. Clin. Infect. Dis. 36, 663–668. 10.1086/367658
    1. Yudin M. H., Landers D. V., Meyn L., Hillier S. L. (2003). Clinical and cervical cytokine response to treatment with oral or vaginal metronidazole for bacterial vaginosis during pregnancy: a randomized trial. Obstet. Gynecol. 102, 527–534. 10.1097/00006250-200309000-00019
    1. Zhu L., Lei A. H., Zheng H. Y., Lyu L. B., Zhang Z. G., Zheng Y. T. (2015). Longitudinal analysis reveals characteristically high proportions of bacterial vaginosis-associated bacteria and temporal variability of vaginal microbiota in northern pig-tailed macaques (Macaca leonina). Zool. Res. 36, 285–298. 10.13918/j.issn.2095-8137.2015.5.285

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