title: Protection against malaria in mice is induced by blood stage-arresting histamine-releasing factor (HRF)-deficient parasites.
abstract: Although most vaccines against blood stage malaria in development today use subunit preparations, live attenuated parasites confer significantly broader and more lasting protection. In recent years, Plasmodium genetically attenuated parasites (GAPs) have been generated in rodent models that cause self-resolving blood stage infections and induce strong protection. All such GAPs generated so far bear mutations in housekeeping genes important for parasite development in red blood cells. In this study, using a Plasmodium berghei model compatible with tracking anti-blood stage immune responses over time, we report a novel blood stage GAP that lacks a secreted factor related to histamine-releasing factor (HRF). Lack of HRF causes an IL-6 increase, which boosts T and B cell responses to resolve infection and leave a cross-stage, cross-species, and lasting immunity. Mutant-induced protection involves a combination of antiparasite IgG2c antibodies and FcγR(+) CD11b(+) cell phagocytes, especially neutrophils, which are sufficient to confer protection. This immune-boosting GAP highlights an important role of opsonized parasite-mediated phagocytosis, which may be central to protection induced by all self-resolving blood stage GAP infections.
authors.affiliation: Unité de Biologie des Interactions Hôte Parasites, Centre National de la Recherche Scientifique ERL9195, Institut National de la Santé et de la Recherche Médicale U1201, Institut Pasteur, F-75015 Paris, France.
authors.forename: Claudia
authors.identifier: 0000-0002-9610-2962
authors.initials: C
authors.lastname: Demarta-Gatsi
authors.affiliation: Unité de Biologie des Interactions Hôte Parasites, Centre National de la Recherche Scientifique ERL9195, Institut National de la Santé et de la Recherche Médicale U1201, Institut Pasteur, F-75015 Paris, France.
authors.forename: Leanna
authors.initials: L
authors.lastname: Smith
authors.affiliation: Unité de Biologie et Génétique du Paludisme, Institut Pasteur, F-75015 Paris, France.
authors.forename: Sabine
authors.identifier: 0000-0001-5507-0602
authors.initials: S
authors.lastname: Thiberge
authors.affiliation: Unité de Biologie des Interactions Hôte Parasites, Centre National de la Recherche Scientifique ERL9195, Institut National de la Santé et de la Recherche Médicale U1201, Institut Pasteur, F-75015 Paris, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Peronet
authors.affiliation: Imagopole, Institut Pasteur, F-75015 Paris, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Commere
authors.affiliation: Spectrométrie de Masse Structurale et Protéomique, Institut Pasteur, F-75015 Paris, France.
authors.forename: Mariette
authors.identifier: 0000-0003-3958-7710
authors.initials: M
authors.lastname: Matondo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U866, Université Bourgogne Franche-Comté et Centre Georges François Leclerc, 21000 Dijon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: Anticorps en Thérapie et Pathologie, Institut National de la Santé et de la Recherche Médicale U1222, Institut Pasteur, F-75015 Paris, France.
authors.forename: Pierre
authors.identifier: 0000-0002-4709-8936
authors.initials: P
authors.lastname: Bruhns
authors.affiliation: Unité de Biologie et Génétique du Paludisme, Institut Pasteur, F-75015 Paris, France.
authors.forename: Robert
authors.identifier: 0000-0001-8603-0603
authors.initials: R
authors.lastname: Ménard
authors.affiliation: Unité de Biologie des Interactions Hôte Parasites, Centre National de la Recherche Scientifique ERL9195, Institut National de la Santé et de la Recherche Médicale U1201, Institut Pasteur, F-75015 Paris, France smecheri@pasteur.fr.
authors.forename: Salaheddine
authors.identifier: 0000-0003-3597-8810
authors.initials: S
authors.lastname: Mécheri
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008288:Malaria / Q000235:genetics / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D000913:Antibodies, Protozoan; D014408:Biomarkers, Tumor; D007074:Immunoglobulin G; D015850:Interleukin-6; D015800:Protozoan Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; C577686:interleukin-6, mouse