title: Complete Plasmodium falciparum liver-stage development in liver-chimeric mice.
abstract: Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2-/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.forename: Alexis
authors.initials: A
authors.lastname: Kaushansky
authors.forename: Nelly
authors.initials: N
authors.lastname: Camargo
authors.forename: John
authors.initials: J
authors.lastname: Bial
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000469:parasitology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000469:parasitology / Q000637:transplantation*; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008018:Life Cycle Stages; D008099:Liver / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000469:parasitology*; D008565:Membrane Proteins; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018512:Parasitemia / Q000469:parasitology*; D010274:Parasitology / Q000379:methods*; D010963:Plasmodium falciparum / Q000235:genetics / Q000254:growth & development*; D015800:Protozoan Proteins; D018183:Transplantation Chimera / Q000469:parasitology*
chemical_list: D004268:DNA-Binding Proteins; C112548:EXP-2 protein, Plasmodium falciparum; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D008565:Membrane Proteins; D015800:Protozoan Proteins; C499308:Rag2 protein, mouse; D006867:Hydrolases; C020156:fumarylacetoacetase