title: Histopathologies, immunolocalization, and a glycan binding screen provide insights into Plasmodium falciparum interactions with the human placenta.
abstract: During pregnancy, Plasmodium falciparum-infected erythrocytes cytoadhere to the placenta. Infection is likely initiated at two sites where placental trophoblasts contact maternal blood: 1) via syncytiotrophoblast (STB), a multicellular transporting and biosynthetic layer that forms the surface of chorionic villi and lines the intervillous space, and 2) through invasive cytotrophoblasts, which line uterine vessels that divert blood to the placenta. Here, we investigated mechanisms of infected erythrocyte sequestration in relationship to the microanatomy of the maternal-fetal interface. Histological analyses revealed STB denudation in placental malaria, which brought the stromal cores of villi in direct contact with maternal blood. STB denudation was associated with hemozoin deposition (P = 0.01) and leukocyte infiltration (P = 0.001) and appeared to be a feature of chronic placental malaria. Immunolocalization of infected red blood cell receptors (CD36, ICAM1/CD54, and chondroitin sulfate A) in placentas from uncomplicated pregnancies showed that STB did not stain, while the underlying villous stroma was immunopositive. Invasive cytotrophoblasts expressed ICAM1. In malaria, STB denudation exposed CD36 and chondroitin sulfate A in the villous cores to maternal blood, and STB expressed ICAM1. Finally, we investigated infected erythrocyte adherence to novel receptors by screening an array of 377 glycans. Infected erythrocytes bound Lewis antigens that immunolocalized to STB. Our results suggest that P. falciparum interactions with STB-associated Lewis antigens could initiate placental malaria. Subsequent pathologies, which expose CD36, ICAM1, and chondroitin sulfate A, might propagate the infection.
authors.affiliation: Department of Obstetrics and Gynecology, the Center for Reproductive Sciences, and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Bethann S
authors.initials: BS
authors.lastname: Hromatka
authors.forename: Sadiki
authors.initials: S
authors.lastname: Ngeleza
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Adibi
authors.forename: Richard K
authors.initials: RK
authors.lastname: Niles
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D000328:Adult; D018955:CD36 Antigens / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism; D002824:Chorionic Villi / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000473:pathology; D010920:Placenta / Q000378:metabolism / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000302:isolation & purification*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000378:metabolism* / Q000473:pathology; D014327:Trophoblasts / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology
chemical_list: D018955:CD36 Antigens; D018799:Intercellular Adhesion Molecule-1; D002809:Chondroitin Sulfates
keywords: placenta; pregnancy; stroma; syncytiotrophoblast; trophoblast