title: Liver-stage development of Plasmodium falciparum, in a humanized mouse model.
abstract: BACKGROUND
  The liver stage of the human malaria parasite Plasmodium falciparum is the least known, yet it holds the greatest promise for the induction of sterile immunity and the development of novel drugs. Progress has been severely limited by the lack of adequate in vitro and in vivo models.
  
  
  METHODS
  Recently, it was found that immunodeficient mice transgenic for the urokinase plasminogen activator allow survival of differentiated human hepatocytes. We confirm this finding but show that hepatocyte survival is short lived unless nonadaptive defenses are simultaneously depleted.
  
  
  RESULTS
  By controlling macrophages and NK cells, we readily effected the long-term secretion of human serum albumin and human alpha-1 antitrypsin in mouse serum (at 3 months, the proportion of repopulated mice increased from 0% to 60% and from 22% to 80%, respectively; P<.0001). P. falciparum sporozoites delivered intravenously into mice readily infected transplanted human hepatocytes and developed into liver schizonts. Their size was twice as large as what was seen in vitro and was comparable to that found in humans and chimpanzees.
  
  
  CONCLUSIONS
  These results emphasize the importance of nonadaptive defenses against xenotransplantation and lead to development of small laboratory models that, because they can harbor human hepatocytes, provide novel opportunities to study intrahepatic pathogens, such as those causing malaria and hepatitis.
authors.affiliation: INSERM U370--Pasteur Institute, CHU Necker, Paris, France.
authors.forename: Serban
authors.initials: S
authors.lastname: Morosan
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hez-Deroubaix
authors.forename: Francoise
authors.initials: F
authors.lastname: Lunel
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.forename: Carlo
authors.initials: C
authors.lastname: Giannini
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Serena
authors.initials: S
authors.lastname: Battaglia
authors.forename: Catherine
authors.initials: C
authors.lastname: Blanc
authors.forename: Wijnand
authors.initials: W
authors.lastname: Eling
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Christian
authors.initials: C
authors.lastname: Brechot
authors.forename: Dina
authors.initials: D
authors.lastname: Kremsdorf
authors.forename: Pierre
authors.initials: P
authors.lastname: Druilhe
mesh_terms: D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage / Q000633:toxicity; D022781:Hepatocytes / Q000469:parasitology / Q000637:transplantation*; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000469:parasitology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D023421:Models, Animal; D010963:Plasmodium falciparum / Q000254:growth & development*; D012709:Serum Albumin / Q000032:analysis; D014183:Transplantation, Heterologous; D000515:alpha 1-Antitrypsin / Q000032:analysis
chemical_list: D012709:Serum Albumin; D000515:alpha 1-Antitrypsin; D004002:Clodronic Acid