Extracellular vesicles from vaginal Gardnerella vaginalis and Mobiluncus mulieris contain distinct proteomic cargo and induce inflammatory pathways.


Journal

NPJ biofilms and microbiomes
ISSN: 2055-5008
Titre abrégé: NPJ Biofilms Microbiomes
Pays: United States
ID NLM: 101666944

Informations de publication

Date de publication:
21 Mar 2024
Historique:
received: 23 12 2023
accepted: 11 03 2024
medline: 22 3 2024
pubmed: 22 3 2024
entrez: 22 3 2024
Statut: epublish

Résumé

Colonization of the vaginal space with bacteria such as Gardnerella vaginalis and Mobiluncus mulieris is associated with increased risk for STIs, bacterial vaginosis, and preterm birth, while Lactobacillus crispatus is associated with optimal reproductive health. Although host-microbe interactions are hypothesized to contribute to reproductive health and disease, the bacterial mediators that are critical to this response remain unclear. Bacterial extracellular vesicles (bEVs) are proposed to participate in host-microbe communication by providing protection of bacterial cargo, delivery to intracellular targets, and ultimately induction of immune responses from the host. We evaluated the proteome of bEVs produced in vitro from G. vaginalis, M. mulieris, and L. crispatus, identifying specific proteins of immunologic interest. We found that bEVs from each bacterial species internalize within cervical and vaginal epithelial cells, and that epithelial and immune cells express a multi-cytokine response when exposed to bEVs from G. vaginalis and M. mulieris but not L. crispatus. Further, we demonstrate that the inflammatory response induced by G. vaginalis and M. mulieris bEVs is TLR2-specific. Our results provide evidence that vaginal bacteria communicate with host cells through secreted bEVs, revealing a mechanism by which bacteria lead to adverse reproductive outcomes associated with inflammation. Elucidating host-microbe interactions in the cervicovaginal space will provide further insight into the mechanisms contributing to microbiome-mediated adverse outcomes and may reveal new therapeutic targets.

Identifiants

pubmed: 38514622
doi: 10.1038/s41522-024-00502-y
pii: 10.1038/s41522-024-00502-y
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

28

Subventions

Organisme : NICHD NIH HHS
ID : R01 HD098867
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD102318
Pays : United States

Informations de copyright

© 2024. The Author(s).

Références

Sun, S. et al. Race, the Vaginal Microbiome, and Spontaneous Preterm Birth. mSystems 7, e0001722 (2022).
pubmed: 35582911 doi: 10.1128/msystems.00017-22
Ravel, J. et al. Vaginal microbiome of reproductive-age women. Proc. Natl Acad. Sci. USA 108, 4680–4687 (2011).
pubmed: 20534435 doi: 10.1073/pnas.1002611107
Valenti, P. et al. Role of Lactobacilli and Lactoferrin in the Mucosal Cervicovaginal Defense. Front Immunol. 9, 376 (2018).
pubmed: 29545798 pmcid: 5837981 doi: 10.3389/fimmu.2018.00376
Hardy, L. et al. The presence of the putative Gardnerella vaginalis sialidase A gene in vaginal specimens is associated with bacterial vaginosis biofilm. PLoS One 12, e0172522 (2017).
pubmed: 28241058 pmcid: 5328246 doi: 10.1371/journal.pone.0172522
Ragaliauskas, T. et al. Inerolysin and vaginolysin, the cytolysins implicated in vaginal dysbiosis, differently impair molecular integrity of phospholipid membranes. Sci. Rep. 9, 10606 (2019).
pubmed: 31337831 pmcid: 6650466 doi: 10.1038/s41598-019-47043-5
Thurman, A. R. et al. Bacterial Vaginosis and Subclinical Markers of Genital Tract Inflammation and Mucosal Immunity. AIDS Res Hum. Retroviruses 31, 1139–1152 (2015).
pubmed: 26204200 pmcid: 4651020 doi: 10.1089/aid.2015.0006
Holst, E., Goffeng, A. R. & Andersch, B. Bacterial vaginosis and vaginal microorganisms in idiopathic premature labor and association with pregnancy outcome. J. Clin. Microbiol. 32, 176–186 (1994).
pubmed: 8126176 pmcid: 262991 doi: 10.1128/jcm.32.1.176-186.1994
Bretelle, F. et al. High Atopobium vaginae and Gardnerella vaginalis vaginal loads are associated with preterm birth. Clin. Infect. Dis. 60, 860–867 (2015).
pubmed: 25452591 doi: 10.1093/cid/ciu966
Hashemi, F. B., Ghassemi, M., Roebuck, K. A. & Spear, G. T. Activation of human immunodeficiency virus type 1 expression by Gardnerella vaginalis. J. Infect. Dis. 179, 924–930 (1999).
pubmed: 10068588 doi: 10.1086/314674
Morrill, S., Gilbert, N. M. & Lewis, A. L. Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models. Front Cell Infect. Microbiol 10, 168 (2020).
pubmed: 32391287 pmcid: 7193744 doi: 10.3389/fcimb.2020.00168
Schwebke, J. R., Muzny, C. A. & Josey, W. E. Role of Gardnerella vaginalis in the pathogenesis of bacterial vaginosis: a conceptual model. J. Infect. Dis. 210, 338–343 (2014).
pubmed: 24511102 doi: 10.1093/infdis/jiu089
Elovitz, M. A. et al. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat. Commun. 10, 1305 (2019).
pubmed: 30899005 pmcid: 6428888 doi: 10.1038/s41467-019-09285-9
Brown, L., Wolf, J. M., Prados-Rosales, R. & Casadevall, A. Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nat. Rev. Microbiol. 13, 620–630 (2015).
pubmed: 26324094 pmcid: 4860279 doi: 10.1038/nrmicro3480
Toyofuku, M., Nomura, N. & Eberl, L. Types and origins of bacterial membrane vesicles. Nat. Rev. Microbiol. 17, 13–24 (2019).
pubmed: 30397270 doi: 10.1038/s41579-018-0112-2
Nahui Palomino, R. A., Vanpouille, C., Costantini, P. E. & Margolis, L. Microbiota-host communications: Bacterial extracellular vesicles as a common language. PLoS Pathog. 17, e1009508 (2021).
pubmed: 33984071 pmcid: 8118305 doi: 10.1371/journal.ppat.1009508
Nahui Palomino, R. A. et al. Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues. Nat. Commun. 10, 5656 (2019).
pubmed: 31827089 pmcid: 6906448 doi: 10.1038/s41467-019-13468-9
Shishpal, P., Kasarpalkar, N., Singh, D. & Bhor, V. M. Characterization of Gardnerella vaginalis membrane vesicles reveals a role in inducing cytotoxicity in vaginal epithelial cells. Anaerobe 61, 102090 (2020).
pubmed: 31442559 doi: 10.1016/j.anaerobe.2019.102090
Shishpal, P., Patel, V., Singh, D. & Bhor, V. M. pH Stress Mediated Alteration in Protein Composition and Reduction in Cytotoxic Potential of Gardnerella vaginalis Membrane Vesicles. Front Microbiol 12, 723909 (2021).
pubmed: 34795647 pmcid: 8593039 doi: 10.3389/fmicb.2021.723909
Artuyants, A., Hong, J., Dauros-Singorenko, P., Phillips, A. & Simoes-Barbosa, A. Lactobacillus gasseri and Gardnerella vaginalis produce extracellular vesicles that contribute to the function of the vaginal microbiome and modulate host-Trichomonas vaginalis interactions. Mol Microbiol (2023). https://doi.org/10.1111/mmi.15130 .
Khan, S., Shishpal, P. & Bhor, V. M. Membrane vesicles of Lactobacillus gasseri ATCC 19992 disrupt biofilms of vaginal pathogens. Anaerobe 82, 102761 (2023).
pubmed: 37467948 doi: 10.1016/j.anaerobe.2023.102761
Costantini, P. E. et al. Extracellular Vesicles Generated by Gram-Positive Bacteria Protect Human Tissues Ex Vivo From HIV-1 Infection. Front Cell Infect. Microbiol 11, 822882 (2021).
pubmed: 35145925 doi: 10.3389/fcimb.2021.822882
Thery, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).
pubmed: 30637094 pmcid: 6322352 doi: 10.1080/20013078.2018.1535750
Zhang, Q., Jeppesen, D. K., Higginbotham, J. N., Franklin, J. L. & Coffey, R. J. Comprehensive isolation of extracellular vesicles and nanoparticles. Nat. Protoc. 18, 1462–1487 (2023).
pubmed: 36914899 doi: 10.1038/s41596-023-00811-0
Kaisanlahti, A. et al. Maternal microbiota communicates with the fetus through microbiota-derived extracellular vesicles. Microbiome 11, 249 (2023).
pubmed: 37953319 pmcid: 10642029 doi: 10.1186/s40168-023-01694-9
Nowak, R. G. et al. Higher Levels of a Cytotoxic Protein, Vaginolysin, in Lactobacillus-Deficient Community State Types at the Vaginal Mucosa. Sex. Transm. Dis. 45, e14–e17 (2018).
pubmed: 29465671 pmcid: 5847449 doi: 10.1097/OLQ.0000000000000774
Macheboeuf, P., Contreras-Martel, C., Job, V., Dideberg, O. & Dessen, A. Penicillin binding proteins: key players in bacterial cell cycle and drug resistance processes. FEMS Microbiol Rev. 30, 673–691 (2006).
pubmed: 16911039 doi: 10.1111/j.1574-6976.2006.00024.x
Tantengco, O. A. G. et al. Exosomes from Ureaplasma parvum-infected ectocervical epithelial cells promote feto-maternal interface inflammation but are insufficient to cause preterm delivery. Front Cell Dev. Biol. 10, 931609 (2022).
pubmed: 36046342 pmcid: 9420848 doi: 10.3389/fcell.2022.931609
Iijima, N., Thompson, J. M. & Iwasaki, A. Dendritic cells and macrophages in the genitourinary tract. Mucosal Immunol. 1, 451–459 (2008).
pubmed: 19079212 pmcid: 2684461 doi: 10.1038/mi.2008.57
Trifonova, R. T., Lieberman, J. & van Baarle, D. Distribution of immune cells in the human cervix and implications for HIV transmission. Am. J. Reprod. Immunol. 71, 252–264 (2014).
pubmed: 24410939 pmcid: 3943534 doi: 10.1111/aji.12198
Yellon, S. M. Immunobiology of Cervix Ripening. Front Immunol. 10, 3156 (2019).
pubmed: 32038651 doi: 10.3389/fimmu.2019.03156
Oliveira-Nascimento, L., Massari, P. & Wetzler, L. M. The Role of TLR2 in Infection and Immunity. Front Immunol. 3, 79 (2012).
pubmed: 22566960 pmcid: 3342043 doi: 10.3389/fimmu.2012.00079
Anton, L. et al. Gardnerella vaginalis alters cervicovaginal epithelial cell function through microbe-specific immune responses. Microbiome 10, 119 (2022).
pubmed: 35922830 pmcid: 9351251 doi: 10.1186/s40168-022-01317-9
Turnbull, L. et al. Explosive cell lysis as a mechanism for the biogenesis of bacterial membrane vesicles and biofilms. Nat. Commun. 7, 11220 (2016).
pubmed: 27075392 pmcid: 4834629 doi: 10.1038/ncomms11220
Bomberger, J. M. et al. Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles. PLoS Pathog. 5, e1000382 (2009).
pubmed: 19360133 pmcid: 2661024 doi: 10.1371/journal.ppat.1000382
Ciofu, O., Beveridge, T. J., Kadurugamuwa, J., Walther-Rasmussen, J. & Hoiby, N. Chromosomal beta-lactamase is packaged into membrane vesicles and secreted from Pseudomonas aeruginosa. J. Antimicrob. Chemother. 45, 9–13 (2000).
pubmed: 10629007 doi: 10.1093/jac/45.1.9
Lee, J. et al. Staphylococcus aureus extracellular vesicles carry biologically active beta-lactamase. Antimicrob. Agents Chemother. 57, 2589–2595 (2013).
pubmed: 23529736 pmcid: 3716153 doi: 10.1128/AAC.00522-12
Mashburn, L. M. & Whiteley, M. Membrane vesicles traffic signals and facilitate group activities in a prokaryote. Nature 437, 422–425 (2005).
pubmed: 16163359 doi: 10.1038/nature03925
Toyofuku, M., Roschitzki, B., Riedel, K. & Eberl, L. Identification of proteins associated with the Pseudomonas aeruginosa biofilm extracellular matrix. J. Proteome Res. 11, 4906–4915 (2012).
pubmed: 22909304 doi: 10.1021/pr300395j
Hajam, I. A., Dar, P. A., Shahnawaz, I., Jaume, J. C. & Lee, J. H. Bacterial flagellin-a potent immunomodulatory agent. Exp. Mol. Med. 49, e373 (2017).
pubmed: 28860663 pmcid: 5628280 doi: 10.1038/emm.2017.172
Carroll-Portillo, A. & Lin, H. C. Bacteriophage and the Innate Immune System: Access and Signaling. Microorganisms 7, 625 (2019).
pubmed: 31795262 pmcid: 6956183 doi: 10.3390/microorganisms7120625
Read, A. D., Bentley, R. E., Archer, S. L. & Dunham-Snary, K. J. Mitochondrial iron-sulfur clusters: Structure, function, and an emerging role in vascular biology. Redox Biol. 47, 102164 (2021).
pubmed: 34656823 pmcid: 8577454 doi: 10.1016/j.redox.2021.102164
Kim, S. W. et al. Significant increase in the secretion of extracellular vesicles and antibiotics resistance from methicillin-resistant Staphylococcus aureus induced by ampicillin stress. Sci. Rep. 10, 21066 (2020).
pubmed: 33273518 pmcid: 7713300 doi: 10.1038/s41598-020-78121-8
Yang, J., Jia, F., Qiao, Y., Hai, Z. & Zhou, X. Correlation between bacterial extracellular vesicles and antibiotics: A potentially antibacterial strategy. Micro. Pathog. 181, 106167 (2023).
doi: 10.1016/j.micpath.2023.106167
Brocklehurst, P., Gordon, A., Heatley, E. & Milan, S. J. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev, CD000262 (2013). https://doi.org/10.1002/14651858.CD000262.pub4 .
Okun, N., Gronau, K. A. & Hannah, M. E. Antibiotics for bacterial vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet. Gynecol. 105, 857–868 (2005).
pubmed: 15802417 doi: 10.1097/01.AOG.0000157108.32059.8f
Sapantzoglou, I. et al. Antibiotic therapy in patients with amniotic fluid sludge and risk of preterm birth: a meta-analysis. Arch Gynecol Obstet, (2023).
Hynonen, U. & Palva, A. Lactobacillus surface layer proteins: structure, function and applications. Appl Microbiol Biotechnol. 97, 5225–5243 (2013).
pubmed: 23677442 pmcid: 3666127 doi: 10.1007/s00253-013-4962-2
Abramov, V. et al. Probiotic Properties of Lactobacillus crispatus 2,029: Homeostatic Interaction with Cervicovaginal Epithelial Cells and Antagonistic Activity to Genitourinary Pathogens. Probiotics Antimicrob. Proteins 6, 165–176 (2014).
pubmed: 25028263 doi: 10.1007/s12602-014-9164-4
Abramov, V. M. et al. S-layer protein 2 of Lactobacillus crispatus 2029, its structural and immunomodulatory characteristics and roles in protective potential of the whole bacteria against foodborne pathogens. Int J. Biol. Macromol. 150, 400–412 (2020).
pubmed: 32045605 doi: 10.1016/j.ijbiomac.2020.02.065
Huttener, M. et al. Roles of Proteins Containing Immunoglobulin-Like Domains in the Conjugation of Bacterial Plasmids. mSphere 7, e0097821 (2022).
pubmed: 34986320 doi: 10.1128/msphere.00978-21
Ojala, T. et al. Comparative genomics of Lactobacillus crispatus suggests novel mechanisms for the competitive exclusion of Gardnerella vaginalis. BMC Genomics 15, 1070 (2014).
pubmed: 25480015 pmcid: 4300991 doi: 10.1186/1471-2164-15-1070
Slattery, L., O’Callaghan, J., Fitzgerald, G. F., Beresford, T. & Ross, R. P. Invited review: Lactobacillus helveticus–a thermophilic dairy starter related to gut bacteria. J. Dairy Sci. 93, 4435–4454 (2010).
pubmed: 20854978 doi: 10.3168/jds.2010-3327
Marrs, C. N. et al. Evidence for Gardnerella vaginalis uptake and internalization by squamous vaginal epithelial cells: implications for the pathogenesis of bacterial vaginosis. Microbes Infect. 14, 500–508 (2012).
pubmed: 22227318 doi: 10.1016/j.micinf.2011.12.009
Chen, J. et al. Inhibitors of Bacterial Extracellular Vesicles. Front. Microbiol. 13, 835058 (2022).
pubmed: 35283837 pmcid: 8905621 doi: 10.3389/fmicb.2022.835058
Eade, C. R. et al. Identification and characterization of bacterial vaginosis-associated pathogens using a comprehensive cervical-vaginal epithelial coculture assay. PLoS One 7, e50106 (2012).
pubmed: 23166828 pmcid: 3499514 doi: 10.1371/journal.pone.0050106
Garcia, E. M., Kraskauskiene, V., Koblinski, J. E. & Jefferson, K. K. Interaction of Gardnerella vaginalis and Vaginolysin with the Apical versus Basolateral Face of a Three-Dimensional Model of Vaginal Epithelium. Infect. Immun. 87, e00646–18 (2019).
pubmed: 30692180 pmcid: 6434120 doi: 10.1128/IAI.00646-18
Herbst-Kralovetz, M. M. et al. Quantification and comparison of toll-like receptor expression and responsiveness in primary and immortalized human female lower genital tract epithelia. Am. J. Reprod. Immunol. 59, 212–224 (2008).
pubmed: 18201283 doi: 10.1111/j.1600-0897.2007.00566.x
Dude, C. M., Saylany, A., Brown, A., Elovitz, M. & Anton, L. Microbial supernatants from Mobiluncus mulieris, a bacteria strongly associated with spontaneous preterm birth, disrupts the cervical epithelial barrier through inflammatory and miRNA mediated mechanisms. Anaerobe 61, 102127 (2020).
pubmed: 31760081 doi: 10.1016/j.anaerobe.2019.102127
Song, J., Lang, F., Zhao, N., Guo, Y. & Zhang, H. Vaginal Lactobacilli Induce Differentiation of Monocytic Precursors Toward Langerhans-like Cells: in Vitro Evidence. Front Immunol. 9, 2437 (2018).
pubmed: 30410487 pmcid: 6211368 doi: 10.3389/fimmu.2018.02437
Xiang, N., Yin, T. & Chen, T. Gardnerella vaginalis induces NLRP3 inflammasome-mediated pyroptosis in macrophages and THP-1 monocytes. Exp. Ther. Med 22, 1174 (2021).
pubmed: 34504619 pmcid: 8393845 doi: 10.3892/etm.2021.10609
Greenwood, J. R. & Pickett, M. J. Transfer of Haemophilus vaginalis Gardner and Dukes to a New Genus, Gardnerella: G. vaginalis (Gardner and Dukes) comb. nov. Int. J. Syst. Evolut. Microbiol. 30, 170–178 (1980).
Spiegel, C. A. & Roberts, M. Mobiluncus gen. nov., Mobiluncus curtisii subsp. curtisii sp. nov., Mobiluncus curtisii subsp. holmesii subsp. nov., and Mobiluncus mulieris sp. nov., Curved Rods from the Human Vagina. Int. J. Syst. Evolut. Microbiol. 34, 177–184 (1984).
Antonio, M. A. & Hillier, S. L. DNA fingerprinting of Lactobacillus crispatus strain CTV-05 by repetitive element sequence-based PCR analysis in a pilot study of vaginal colonization. J. Clin. Microbiol. 41, 1881–1887 (2003).
pubmed: 12734221 pmcid: 154705 doi: 10.1128/JCM.41.5.1881-1887.2003
Felice, A. G., Sousa, E. G., Dominici, F. V., Azevedo, V. A. D. C. & Soares, S. D. C. Pangenome Analysis Reveals a High Degree of Genetic Diversity in Gardnerella vaginalis: An In Silico Approach. Venereology 2, 132–146 (2023).
doi: 10.3390/venereology2040012
Tiveljung, A., Forsum, U. & Monstein, H.-J. Classification of the Genus Mobiluncus Based on Comparative Partial 16S rRNA Gene Analysis. Int. J. Syst. Evolut. Microbiol. 46, 332–336 (1996).
Edwards, V. L. et al. The Cervicovaginal Microbiota-Host Interaction Modulates Chlamydia trachomatis Infection. mBio 10, e01548–19 (2019).
pubmed: 31409678 pmcid: 6692509 doi: 10.1128/mBio.01548-19
Argentini, C. et al. Evaluation of Modulatory Activities of Lactobacillus crispatus Strains in the Context of the Vaginal Microbiota. Microbiol. Spectr. 10, e0273321 (2022).
pubmed: 35266820 doi: 10.1128/spectrum.02733-21
Zhang, K. et al. Antibiotic resistance and pathogenicity assessment of various Gardnerella sp. strains in local China. Front. Microbiol. 13, 1009798 (2022).
pubmed: 36225381 pmcid: 9549249 doi: 10.3389/fmicb.2022.1009798
Zougman, A., Selby, P. J. & Banks, R. E. Suspension trapping (STrap) sample preparation method for bottom-up proteomics analysis. Proteomics 14, 1006–1000 (2014).
pubmed: 24678027 doi: 10.1002/pmic.201300553
Bielow, C., Mastrobuoni, G. & Kempa, S. Proteomics Quality Control: Quality Control Software for MaxQuant Results. J. Proteome Res 15, 777–787 (2016).
pubmed: 26653327 doi: 10.1021/acs.jproteome.5b00780
Tyanova, S., Temu, T. & Cox, J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat. Protoc. 11, 2301–2319 (2016).
pubmed: 27809316 doi: 10.1038/nprot.2016.136
Lau, W. Y. V. et al. PSORTdb 4.0: expanded and redesigned bacterial and archaeal protein subcellular localization database incorporating new secondary localizations. Nucleic Acids Res. 49, D803–D808 (2021).
pubmed: 33313828 doi: 10.1093/nar/gkaa1095
Cantalapiedra, C. P., Hernandez-Plaza, A., Letunic, I., Bork, P. & Huerta-Cepas, J. eggNOG-mapper v2: Functional Annotation, Orthology Assignments, and Domain Prediction at the Metagenomic Scale. Mol. Biol. Evol. 38, 5825–5829 (2021).
pubmed: 34597405 pmcid: 8662613 doi: 10.1093/molbev/msab293
Emms, D. M. & Kelly, S. OrthoFinder: phylogenetic orthology inference for comparative genomics. Genome Biol. 20, 238 (2019).
pubmed: 31727128 pmcid: 6857279 doi: 10.1186/s13059-019-1832-y

Auteurs

Andrea Joseph (A)

Women's Biomedical Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA. andrea.joseph@mssm.edu.
Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA. andrea.joseph@mssm.edu.

Lauren Anton (L)

Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Yuxia Guan (Y)

Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Briana Ferguson (B)

Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Isabella Mirro (I)

Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Nova Meng (N)

Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Michael France (M)

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Jacques Ravel (J)

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Michal A Elovitz (MA)

Women's Biomedical Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.

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