title: Inactivation of a Plasmodium apicoplast protein attenuates formation of liver merozoites.
abstract: Malaria parasites undergo a population expansion inside the host liver before disease onset. Developmental arrest inside host hepatocytes elicits protective immune responses. Therefore, elucidation of the molecular mechanisms leading to mature hepatic merozoites, which initiate the pathogenic blood phase, also informs anti-malaria vaccine strategies. Using targeted gene deletion in the rodent model malaria parasite Plasmodium berghei, we show that a Plasmodium-specific Apicoplast protein plays an important role for Liver Merozoite formation (PALM). While the resulting knockout mutants develop normally for most of the life cycle, merozoite release into the blood stream and the ability to establish an infection are severely impaired. Presence of a signature blood-stage antigen, merozoite surface protein 1 and normal apicoplast morphology indicate that the inability to finalize merozoite segregation is a direct consequence of loss of PALM function. Experimental immunization of mice with as few as two doses of palm(-) sporozoites can elicit sterile protection up to 110 days after final immunization. Our data establish that a tailor-made arrest in the final steps of hepatic merozoite formation can induce strong protective immune responses and that malaria parasites employ a distinct apicoplast protein for efficient formation of pre-erythrocytic merozoites.
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Haussig
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.forename: Taco W A
authors.initials: TW
authors.lastname: Kooij
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000469:parasitology / Q000473:pathology; D017780:Malaria Vaccines / Q000276:immunology; D052940:Merozoites / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010962:Plasmodium berghei / Q000235:genetics / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014613:Vaccines, Attenuated / Q000276:immunology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014613:Vaccines, Attenuated; D037521:Virulence Factors