title: Disruption of plasmepsin-4 and merozoites surface protein-7 genes in Plasmodium berghei induces combined virulence-attenuated phenotype.
abstract: Blood stage malaria parasites causing a mild and self limited infection in mice have been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. Targeted disruption of plasmepsin-4 (pm4) or the merozoite surface protein-7 (msp7) genes also induces a virulence-attenuated phenotype in terms of absence of experimental cerebral malaria (ECM), delayed increase of parasitemia and reduced mortality rate. The decrease in virulence in parasites lacking either pm4 or msp7 is however incomplete and dependent on the parasite and mouse strain combination. The sequential disruption of both genes induced remarkable virulence-attenuated blood-stage parasites characterized by a self-resolving infection with low levels of parasitemia and no ECM. Furthermore, convalescent mice were protected against the challenge with P. berghei or P. yoelii parasites for several months. These observations provide a proof-of-concept step for the development of human malaria vaccines based on genetically attenuated blood-stage parasites.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Via Del Giochetto, 06126 Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.forename: Elena
authors.initials: E
authors.lastname: Aime
authors.forename: Sara
authors.initials: S
authors.lastname: Caterbi
authors.forename: Paola
authors.initials: P
authors.lastname: Arcidiacono
authors.forename: Barbara
authors.initials: B
authors.lastname: Capuccini
authors.forename: Manlio
authors.initials: M
authors.lastname: Di Cristina
authors.forename: Tania
authors.initials: T
authors.lastname: Dottorini
authors.forename: Mario
authors.initials: M
authors.lastname: Rende
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020868:Gene Silencing; D008288:Malaria / Q000469:parasitology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000378:metabolism* / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D015800:Protozoan Proteins; D037521:Virulence Factors; C439571:merozoite surface protein 7, Plasmodium; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin