Complete Plasmodium falciparum liver stage development in liver-chimeric mice

The Journal of clinical investigation (Impact Factor: 13.77). 09/2012; 122(10):3618-28. DOI: 10.1172/JCI62684
Source: PubMed

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.

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Available from: Ashley M Vaughan, Dec 18, 2013
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    • "Replacement indices of N 90% can be achieved (Azuma et al., 2007; Hasegawa et al., 2011; Hu et al., 2013; Dandri et al., 2001; Tateno et al., 2004). Liver chimeric mice have been used to study infections (Dandri et al., 2001; Bissig et al., 2010; Mercer et al., 2001; Morosan et al., 2006; Vaughan et al., 2012; Kawahara et al., 2013), drug metabolism (Tanoue et al., 2013; Sanoh et al., 2012), gene therapy (Lisowski et al., 2014) and hepatic stem cells (Duncan et al., 2012; Takebe et al., 2013; Zhu et al., 2014). Importantly however, many normal and pathophysiologic processes in the liver involve interactions between blood derived cells and hepatic epithelial cells. "
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    • "Salivary gland dissections were performed at days 14–19. Production of P. falciparum sporozoites and the infection of FRG KO huHep mice with P. falciparum were performed as previously described (Vaughan et al., 2012). "
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    • "Detection of PTEX components in gametocytes, sporozoites, and late liver stages (Vaughan et al., 2012; Matthews et al., 2013) indicates that the putative translocation machinery is available during these stages of infection. For instance, two core PTEX components, PTEX150, and EXP2 (de Koning-Ward et al., 2009), localize to the parasite/host interface in mature P. falciparum liver-stage parasites in human hepatocytes from infected liver-chimeric mice (Vaughan et al., 2012). PTEX150, EXP2 and the third core PTEX protein HSP101 are present in P. berghei salivary gland sporozoites and liver-stage merozoites in cultured hepatoma cells (Matthews et al., 2013). "
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