title: Plasmodium falciparum infection and exoerythrocytic development in mice with chimeric human livers.
abstract: The exoerythrocytic stage of Plasmodium falciparum has remained a difficult phase of the parasite life-cycle to study. The host and tissue specificity of the parasite requires the experimental infection of humans or non-human primates and subsequent surgical recovery of parasite-infected liver tissue to analyze this stage of the parasites development. This type of study is impossible in humans due to obvious ethical considerations and the cost and complexity in working with primate models has precluded their use for extensive studies of the exoerythrocytic stage. In this study we assessed, for the first time, the use of transgenic, chimeric mice containing functioning human hepatocytes as an alternative for modeling the in vivo interaction of P. falciparum parasites and human hepatocytes. Infection of these mice with P. falciparum sporozoites produced morphologically and antigenically mature liver stage schizonts containing merozoites capable of invading human red blood cells. Additionally, using microdissection, highly enriched P. falciparum liver stage parasites essentially free of hepatocyte contamination, were recovered for molecular studies. Our results establish a stable murine model for P. falciparum that will have a wide utility for assessing the biology of the parasite, potential anti-malarial chemotherapeutic agents and vaccine design.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA. jsacc001@umaryland.edu
authors.forename: John B
authors.initials: JB
authors.lastname: Sacci
authors.forename: Uzma
authors.initials: U
authors.lastname: Alam
authors.forename: Donna
authors.initials: D
authors.lastname: Douglas
authors.forename: Jamie
authors.initials: J
authors.lastname: Lewis
authors.forename: D Lorne J
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: Abdu F
authors.initials: AF
authors.lastname: Azad
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000032:analysis; D002678:Chimera / Q000235:genetics*; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000502:physiology*; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000235:genetics; D017125:Genes, Protozoan / Q000235:genetics; D022781:Hepatocytes / Q000502:physiology; D006790:Host-Parasite Interactions; D006801:Humans; D008099:Liver / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology*; D016778:Malaria, Falciparum / Q000503:physiopathology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D042282:Microdissection / Q000379:methods; D010963:Plasmodium falciparum / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D034101:Sporozoites / Q000502:physiology
chemical_list: D000953:Antigens, Protozoan