title: Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.
abstract: Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS) can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS) depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both P. falciparum and rodent malaria Plasmodium species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ben C L
authors.initials: BC
authors.lastname: van Schaijk
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.forename: Melissa R
authors.initials: MR
authors.lastname: van Dijk
authors.forename: Audrey
authors.initials: A
authors.lastname: Gego
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Franetich
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.forename: Samir
authors.initials: S
authors.lastname: Yalaoui
authors.forename: Olivier
authors.initials: O
authors.lastname: Silvie
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Waters
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Khan
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D009033:Culicidae / Q000469:parasitology; D018390:Gene Targeting; D015316:Genetic Therapy; D022781:Hepatocytes / Q000469:parasitology*; D006801:Humans; D008018:Life Cycle Stages / Q000235:genetics*; D008099:Liver / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000469:parasitology / Q000628:therapy*; D010962:Plasmodium berghei / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics / Q000254:growth & development*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000953:Antigens, Protozoan