title: Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.
abstract: Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Deltapm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Real-time in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Via Del Giochetto, 06122 Perugia, Italy. roberta.spaccapelo@unipg.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.forename: Sara
authors.initials: S
authors.lastname: Caterbi
authors.forename: Blandine
authors.initials: B
authors.lastname: Franke-Fayard
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Bonilla
authors.forename: Luke M
authors.initials: LM
authors.lastname: Syphard
authors.forename: Manlio
authors.initials: M
authors.lastname: Di Cristina
authors.forename: Tania
authors.initials: T
authors.lastname: Dottorini
authors.forename: Andrea
authors.initials: A
authors.lastname: Savarino
authors.forename: Antonio
authors.initials: A
authors.lastname: Cassone
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Waters
authors.forename: John B
authors.initials: JB
authors.lastname: Dame
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000378:metabolism; D001921:Brain / Q000469:parasitology / Q000473:pathology; D007109:Immunity / Q000276:immunology*; D008018:Life Cycle Stages; D008156:Luciferases / Q000378:metabolism; D008288:Malaria / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010271:Parasites / Q000201:enzymology / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D010641:Phenotype; D010962:Plasmodium berghei / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D013154:Spleen / Q000276:immunology / Q000469:parasitology; D014774:Virulence / Q000276:immunology
chemical_list: D000906:Antibodies; D008156:Luciferases; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin