title: The villain team-up or how Trichomonas vaginalis and bacterial vaginosis alter innate immunity in concert.
abstract: OBJECTIVE
  Complex interactions of vaginal microorganisms with the genital tract epithelium shape mucosal innate immunity, which holds the key to sexual and reproductive health. Bacterial vaginosis (BV), a microbiome-disturbance syndrome prevalent in reproductive-age women, occurs commonly in concert with trichomoniasis, and both are associated with increased risk of adverse reproductive outcomes and viral infections, largely attributable to inflammation. To investigate the causative relationships among inflammation, BV and trichomoniasis, we established a model of human cervicovaginal epithelial cells colonised by vaginal Lactobacillus isolates, dominant in healthy women, and common BV species (Atopobium vaginae, Gardnerella vaginalis and Prevotella bivia).
  
  
  METHODS
  Colonised epithelia were infected with Trichomonas vaginalis (TV) or exposed to purified TV virulence factors (membrane lipophosphoglycan (LPG), its ceramide-phosphoinositol-glycan core (CPI-GC) or the endosymbiont Trichomonas vaginalis virus (TVV)), followed by assessment of bacterial colony-forming units, the mucosal anti-inflammatory microbicide secretory leucocyte protease inhibitor (SLPI), and chemokines that drive pro-inflammatory, antigen-presenting and T cells.
  
  
  RESULTS
  TV reduced colonisation by Lactobacillus but not by BV species, which were found inside epithelial cells. TV increased interleukin (IL)-8 and suppressed SLPI, likely via LPG/CPI-GC, and upregulated IL-8 and RANTES, likely via TVV as suggested by use of purified pathogenic determinants. BV species A vaginae and G vaginalis induced IL-8 and RANTES, and also amplified the pro-inflammatory responses to both LPG/CPI-GC and TVV, whereas P bivia suppressed the TV/TVV-induced chemokines.
  
  
  CONCLUSIONS
  These molecular host-parasite-endosymbiont-bacteria interactions explain epidemiological associations and suggest a revised paradigm for restoring vaginal immunity and preventing BV/TV-attributable inflammatory sequelae in women.
authors.affiliation: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. rfichorova@rics.bwh.harvard.edu
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Buck
authors.forename: Hidemi S
authors.initials: HS
authors.lastname: Yamamoto
authors.forename: Titilayo
authors.initials: T
authors.lastname: Fashemi
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Dawood
authors.forename: Bisiayo
authors.initials: B
authors.lastname: Fashemi
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hayes
authors.forename: David H
authors.initials: DH
authors.lastname: Beach
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Mary L
authors.initials: ML
authors.lastname: Delaney
authors.forename: Max L
authors.initials: ML
authors.lastname: Nibert
authors.forename: Bibhuti N
authors.initials: BN
authors.lastname: Singh
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Onderdonk
mesh_terms: D001419:Bacteria / Q000276:immunology* / Q000472:pathogenicity; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D015169:Colony Count, Microbial; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D056265:Microbial Interactions; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D014246:Trichomonas vaginalis / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D018925:Chemokines; D053481:Secretory Leukocyte Peptidase Inhibitor
keywords: BACTERIAL VAGINOSIS; IMMUNOLOGY; TRICHOMONAS; VAGINAL MICROBIOLOGY; WOMEN
references.citation: Infect Immun. 2000 Jul;68(7):4200-6
references.pmid: 10858237
references.citation: Biol Reprod. 1997 Oct;57(4):847-55
references.pmid: 9314589
references.citation: Best Pract Res Clin Obstet Gynaecol. 2007 Jun;21(3):347-54
references.pmid: 17215167
references.citation: J Biol Chem. 2011 Nov 25;286(47):40494-508
references.pmid: 21900246
references.citation: J Infect Dis. 2006 Aug 15;194(4):498-502
references.pmid: 16845634
references.citation: J Clin Microbiol. 2003 Mar;41(3):1073-9
references.pmid: 12624032
references.citation: PLoS One. 2012;7(11):e48418
references.pmid: 23144878
references.citation: BMC Microbiol. 2004 Apr 21;4:16
references.pmid: 15102329
references.citation: Sex Transm Infect. 2008 Feb;84(1):57-61
references.pmid: 17911138
references.citation: mBio. 2011 Oct 25;2(6):e00168-11
references.pmid: 22027006
references.citation: J Reprod Immunol. 2009 Dec;83(1-2):185-9
references.pmid: 19850356
references.citation: Sex Transm Dis. 2012 Oct;39(10):807-12
references.pmid: 23007708
references.citation: J Acquir Immune Defic Syndr. 2012 May 1;60(1):12-9
references.pmid: 22240462
references.citation: Cochrane Database Syst Rev. 2009 Oct 07;(4):CD006289
references.pmid: 19821358
references.citation: Antimicrob Agents Chemother. 2009 Apr;53(4):1490-500
references.pmid: 19139286
references.citation: Cell. 1997 Feb 7;88(3):417-26
references.pmid: 9039268
references.citation: J Infect Dis. 2008 Oct 15;198(8):1131-40
references.pmid: 18717638
references.citation: Clin Vaccine Immunol. 2007 Sep;14(9):1102-7
references.pmid: 17671228
references.citation: Sci Transl Med. 2012 May 2;4(132):132ra52
references.pmid: 22553250
references.citation: PLoS One. 2012;7(6):e37818
references.pmid: 22719852
references.citation: Glycoconj J. 2009 Jan;26(1):3-17
references.pmid: 18604640
references.citation: Infect Immun. 2006 Oct;74(10):5773-9
references.pmid: 16988255
references.citation: Biol Reprod. 1999 Feb;60(2):508-14
references.pmid: 9916021
references.citation: BMC Microbiol. 2005 Oct 14;5:61
references.pmid: 16225680
references.citation: J Immunol. 2002 Mar 1;168(5):2424-32
references.pmid: 11859134
references.citation: Appl Environ Microbiol. 1987 Dec;53(12):2779-84
references.pmid: 3435143
references.citation: BMC Microbiol. 2013 Jan 08;13:4
references.pmid: 23298379
references.citation: Arch Intern Med. 1989 Mar;149(3):565-8
references.pmid: 2645843
references.citation: J Infect Dis. 2013 May 1;207(9):1462-70
references.pmid: 23355743