Further Improvements of the P. falciparum Humanized Mouse Model

Abstract

BackgroundIt has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines.Materials/MethodsWe investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2Rγ deficiency (NSG mice).ResultsWe demonstrate here the role of aging, of inosine and of the IL-2 receptor γ mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent.ConclusionThe combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.

Passive Immunoprotection of Plasmodium falciparum-Infected Mice Designates the CyRPA as Candidate Malaria Vaccine Antigen

“…Because P. falciparum cannot infect rodent erythrocytes and rodent malaria parasites lack many Ags of P. falciparum, including CyRPA, nonhuman primates or SCID-mice engrafted with human erythrocytes are the only in vivo models available to study growth inhibitory effects of CyRPA-specific Abs. It was previously shown that the P. falciparum model in NOD-SCID mice genetically deficient in IL-2R g-chain (NODscid IL2Rg null ) engrafted with human erythrocytes is a reliable test system for drug evaluation in vivo (65,80). Also in our hands, parasite growth in infected NOD-scid IL2Rg null mice was very consistent and reproducible.…”

Complete Plasmodium falciparum liver-stage development in liver-chimeric mice

“…Immunocompromised mice into which hurbc are continuously injected are able to support P. falciparum blood-stage infections, but the drawbacks are that the mice either have to be infected with adapted strains of P. falciparum (36) or continuously treated with clodronate liposomes to deplete macrophages (37). If the FRG NOD huHep mouse was also used for hurbc reconstitution, the clodronate depletion of the resident macrophages in the liver, the Kupffer cells, might have an effect on liver infection by sporozoites.…”

Stem cell-derived cell cultures and organoids for protozoan parasite propagation and studying host–parasite interaction

“…A further application of this technology is to humanize mice with such cells (Arnold et al, 2011;Legrand et al, 2009) in order to study many aspects of host-parasite relation in vivo in an unprecedented way. The generation of mice with gene defects that prevent formation of T and B cells (scid or rag mutations) and natural killer cells (through IL-2 receptor γ chain deficiency) resulted in models that sustain meaningful numbers of human blood cells (Ito et al, 2002;Traggiai et al, 2004), and these models are continuously being improved (Brehm et al, 2012;Strowig and Flavell, 2012).…”