title: Immunoglobulin response to Plasmodium falciparum RESA proteins in uncomplicated and severe malaria.
abstract: BACKGROUND
  The three members of the ring-infected erythrocyte surface antigen (RESA) proteins family share high sequence homologies, which impair the detection and assignment to one or another protein of some pathogenic processes inherent to Plasmodium falciparum malaria. The present study was intended to determine if the antibody and inflammatory responses of children living in a malaria-endemic area varied depending on the RESA-1, RESA-2 or RESA-3 proteins and the severity of the disease, two groups of severe and uncomplicated malaria cases being considered.
  
  
  METHODS
  Two synthetic peptides representing predicted B cell epitopes were designed per RESA protein, all located outside of the 3' and 5' repetition blocks, in order to allow an antibody detection specific of each member of the family. Recombinant rRESA-1B and rRESA-3B proteins were also engineered. Two groups of Beninese children admitted to hospital in 2009 for either uncomplicated or severe malaria were compared for their plasma levels of IgG specifically recognizing each recombinant RESA protein or synthetic peptide, and for their plasma inflammatory cytokine levels (IFN-γ, TNF-α and IL-10), taking into account host and parasite genetic factors.
  
  
  RESULTS
  The absence of IgG cross-reactivity between rRESA proteins and their protein carrier as well as between each RESA peptide and a non-epitopic RESA control peptide validated the use of the engineered recombinant proteins and peptides for the measurement of plasma IgG. Taking into account age, fever duration and parasitaemia, a multiple logistic regression performed on children clustered according to their antibody responses' profiles concluded to an increased risk of severe malaria for P2 (representative of RESA-1) responders (P = 0.007). Increased IL-10 plasma levels were found in children harbouring multiclonal P. falciparum infections on the basis of the T1526G resa2 gene polymorphism (P = 0.004).
  
  
  CONCLUSIONS
  This study provided novel tools to dissect the seroreactivity against the three members of the RESA protein family and to describe its relation to protection against malaria. It suggested the measurement of plasma antibodies raised against specific peptides to serve as predictive immunologic markers for disease severity. Lastly, it reinforced previous observations linking the T1526G resa2 gene mutation to severe malaria.
authors.affiliation: Equipe résidente de recherche en infectiologie tropicale, Institut de Recherche Biomédicale des Armées (IRBA), Brétigny sur Orge, France. cbadaut@gmail.com.
authors.forename: Cyril
authors.initials: C
authors.lastname: Badaut
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. lea.guyonnet@voila.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. lea.guyonnet@voila.fr.|Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM) U970, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. lea.guyonnet@voila.fr.
authors.forename: Léa
authors.initials: L
authors.lastname: Guyonnet
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. jacqueline.milet@ird.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. jacqueline.milet@ird.fr.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Milet
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. Emmanuelle.Renard@ac-creteil.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. Emmanuelle.Renard@ac-creteil.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Renard
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. remy.durand@avc.aphp.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. remy.durand@avc.aphp.fr.|Laboratoire de Parasitologie-Mycologie, Hôpital Avicenne, AP-HP, Bobigny, France. remy.durand@avc.aphp.fr.
authors.forename: Rémy
authors.initials: R
authors.lastname: Durand
authors.affiliation: Centre d'Étude et de Recherche sur le Paludisme Associé à la Grossesse et l'Enfance (CERPAGE), Cotonou, Benin. vfeafr@yahoo.fr.
authors.forename: Firmine
authors.initials: F
authors.lastname: Viwami
authors.affiliation: Service de Pédiatrie, Centre National Hospitalier et Universitaire Hubert K. Maga, Cotonou, Benin. godsagbo@yahoo.fr.
authors.forename: Gratien
authors.initials: G
authors.lastname: Sagbo
authors.affiliation: Service de Pédiatrie, Centre National Hospitalier et Universitaire Hubert K. Maga, Cotonou, Benin. lalyahf@hotmail.com.
authors.forename: Francis
authors.initials: F
authors.lastname: Layla
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. philippe.deloron@ird.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. philippe.deloron@ird.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.affiliation: Unité de Biologie Cellulaire des Trypanosomes, Institut Pasteur, INSERM U1201, Paris, France. serge.bonnefoy@pasteur.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Bonnefoy
authors.affiliation: Institut de Recherche pour le Développement, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. florence.migot-nabias@ird.fr.|COMUE Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. florence.migot-nabias@ird.fr.|Faculté de Pharmacie, IRD UMR216, 4 avenue de l'Observatoire, 75006, Paris, France. florence.migot-nabias@ird.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Migot-Nabias
mesh_terms: D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D001541:Benin / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology*; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D016207:Cytokines; D007074:Immunoglobulin G; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C050256:ring-infected erythrocyte surface antigen (RESA), Plasmodium falciparum