title: Trichomonas vaginalis Lipophosphoglycan Exploits Binding to Galectin-1 and -3 to Modulate Epithelial Immunity.
abstract: Trichomoniasis is the most common non-viral sexually transmitted infection caused by the vaginotropic extracellular protozoan parasite Trichomonas vaginalis. The infection is recurrent, with no lasting immunity, often asymptomatic, and linked to pregnancy complications and risk of viral infection. The molecular mechanisms of immune evasion by the parasite are poorly understood. We demonstrate that galectin-1 and -3 are expressed by the human cervical and vaginal epithelial cells and act as pathogen-recognition receptors for the ceramide phosphoinositol glycan core (CPI-GC) of the dominant surface protozoan lipophosphoglycan (LPG). We used an in vitro model with siRNA galectin knockdown epithelial clones, recombinant galectins, clinical Trichomonas isolates, and mutant protozoan derivatives to dissect the function of galectin-1 and -3 in the context of Trichomonas infection. Galectin-1 suppressed chemokines that facilitate recruitment of phagocytes, which can eliminate extracellular protozoa (IL-8) or bridge innate to adaptive immunity (MIP-3α and RANTES (regulated on activation normal T cell expressed and secreted)). Silencing galectin-1 increased and adding exogenous galectin-1 suppressed chemokine responses to Trichomonas or CPI-GC/LPG. In contrast, silencing galectin-3 reduced IL-8 response to LPG. Live Trichomonas depleted the extracellular levels of galectin-3. Clinical isolates and mutant Trichomonas CPI-GC that had reduced affinity to galectin-3 but maintained affinity to galectin-1 suppressed chemokine expression. Thus via CPI-GC binding, Trichomonas is capable of regulating galectin bioavailability and function to the benefit of its parasitic survival. These findings suggest novel approaches to control trichomoniasis and warrant further studies of galectin-binding diversity among clinical isolates as a possible source for symptom disparity in parasitic infections.
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, rfichorova@rics.bwh.harvard.edu.
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Hidemi S
authors.initials: HS
authors.lastname: Yamamoto
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Titilayo
authors.initials: T
authors.lastname: Fashemi
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Evan
authors.initials: E
authors.lastname: Foley
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Stanthia
authors.initials: S
authors.lastname: Ryan
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Noah
authors.initials: N
authors.lastname: Beatty
authors.affiliation: From the Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Hassan
authors.initials: H
authors.lastname: Dawood
authors.affiliation: the Departments of Biochemistry and Molecular Biology and Obstetrics and Gynecology, State University of New York Upstate Medical University, Syracuse, New York 13210, and.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hayes
authors.affiliation: the Laboratory of Glycobiology and Bioimaging, Research Centre for Infectious Diseases, Faculty of Medicine, Laval University, Quebec, Quebec G1V 4G2, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: St-Pierre
authors.affiliation: the Laboratory of Glycobiology and Bioimaging, Research Centre for Infectious Diseases, Faculty of Medicine, Laval University, Quebec, Quebec G1V 4G2, Canada.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Sato
authors.affiliation: the Departments of Biochemistry and Molecular Biology and Obstetrics and Gynecology, State University of New York Upstate Medical University, Syracuse, New York 13210, and.
authors.forename: Bibhuti N
authors.initials: BN
authors.lastname: Singh
mesh_terms: D002460:Cell Line; D002584:Cervix Uteri / Q000469:parasitology / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000469:parasitology*; D005260:Female; D037483:Galectin 1 / Q000378:metabolism*; D037502:Galectin 3 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D007109:Immunity; D007700:Kinetics; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D014246:Trichomonas vaginalis / Q000302:isolation & purification / Q000378:metabolism*; D014621:Vagina / Q000469:parasitology / Q000473:pathology
chemical_list: D018925:Chemokines; D037483:Galectin 1; D037502:Galectin 3; D006028:Glycosphingolipids; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C008290:lipophosphonoglycan
keywords: CCL-20 (MIP-3α); CCL5 (RANTES); Interleukin 8 (IL-8); cytokine; galectin; human vagina; inflammation; interleukin; parasite; sexually transmitted infection