Liver-Stage Development of Plasmodium falciparum in a Humanized Mouse Model
S Morosan, S Hez-Deroubaix, F Lunel… - The Journal of …, 2006 - academic.oup.com
The Journal of infectious diseases, 2006•academic.oup.com
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 …
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 …
Abstract
BackgroundThe 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
MethodsRecently, 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
ResultsBy controlling macrophages and NK cells, we readily effected the long-term secretion of human serum albumin and human α-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
ConclusionThese 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
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