title: Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy.
abstract: Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 10(4) P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei At doses of 10(5) and 10(6) IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6-EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal lmoraes@igc.gulbenkian.pt B.Franke-Fayard@lumc.nl.
authors.forename: Luciana V
authors.initials: LV
authors.lastname: de Moraes
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Dechavanne
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Sousa
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Barateiro
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Sónia F
authors.initials: SF
authors.lastname: Cunha
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Sofia
authors.initials: S
authors.lastname: Nunes-Silva
authors.affiliation: Departamento de Parasitologia, Universidade de São Paulo-ICB/USP, São Paulo, SP, Brazil.
authors.forename: Flávia A
authors.initials: FA
authors.lastname: Lima
authors.affiliation: Departamento de Parasitologia, Universidade de São Paulo-ICB/USP, São Paulo, SP, Brazil.
authors.forename: Oscar
authors.initials: O
authors.lastname: Murillo
authors.affiliation: Departamento de Parasitologia, Universidade de São Paulo-ICB/USP, São Paulo, SP, Brazil.
authors.forename: Claudio R F
authors.initials: CRF
authors.lastname: Marinho
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gangnard
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Anand
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joanna A
authors.initials: JA
authors.lastname: Braks
authors.affiliation: Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gamain
authors.affiliation: Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands lmoraes@igc.gulbenkian.pt B.Franke-Fayard@lumc.nl.
authors.forename: Blandine
authors.initials: B
authors.lastname: Franke-Fayard
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Penha-Gonçalves
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D008288:Malaria / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016778:Malaria, Falciparum / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D018512:Parasitemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D010920:Placenta; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000072417:Protein Domains; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D050497:Stillbirth
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D000939:Epitopes; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; D002809:Chondroitin Sulfates