Liver-stage development of Plasmodium falciparum, in a humanized mouse model.
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.
Morosan
Serban
S
INSERM U370--Pasteur Institute, CHU Necker, Paris, France.
Hez-Deroubaix
Stéphanie
S
Lunel
Francoise
F
Renia
Laurent
L
Giannini
Carlo
C
Van Rooijen
Nico
N
Battaglia
Serena
S
Blanc
Catherine
C
Eling
Wijnand
W
Sauerwein
Robert
R
Hannoun
Laurent
L
Belghiti
Jacques
J
Brechot
Christian
C
Kremsdorf
Dina
D
Druilhe
Pierre
P
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
D012709:Serum Albumin; D000515:alpha 1-Antitrypsin; D004002:Clodronic Acid