The invention of liver-humanized mouse models has made it possible to directly study the preerythrocytic stages of Plasmodium falciparum. In contrast, the current models to directly study blood stage
infection in vivo are extremely limited. Humanization of the mouse blood stream is achievable by frequent
injections of human red blood cells (hRBCs) and is currently the only system with which to study human
malaria blood stage
infections in a small animal model.
Infections have been primarily achieved by direct injection of P. falciparum-infected RBCs but as such, this modality of
infection does not model the natural route of
infection by mosquito
bite and lacks the transition of parasites from liver stage
infection to blood stage
infection. Including these life cycle transition points in a small animal model is of relevance for testing therapeutic interventions. To this end, we used FRGN KO mice that were engrafted with human hepatocytes and performed a blood exchange under immune modulation to engraft the animals with more than 50% hRBCs. These mice were infected by mosquito
bite with sporozoite stages of a
luciferase-expressing P. falciparum parasite, resulting in noninvasively measurable liver stage burden by in vivo bioluminescent imaging (IVIS) at days 5-7 postinfection. Transition to blood stage
infection was observed by IVIS from day 8 onward and then blood stage
parasitemia increased with a kinetic similar to that observed in controlled human
malaria infection. To assess the utility of this model, we tested whether a
monoclonal antibody targeting the erythrocyte invasion
ligand reticulocyte-
binding protein homolog 5 (with known growth inhibitory activity in vitro) was capable of blocking blood stage
infection in vivo when parasites emerge from the liver and found it highly effective. Together, these results show that a combined liver-humanized and blood-humanized FRGN mouse model infected with
luciferase-expressing P. falciparum will be a useful tool to study P. falciparum preerythrocytic and erythrocytic stages and enables the testing of interventions that target either one or both stages of
parasite infection.