Humanized mice for sustained Plasmodium vivax blood-stage infection and transmission

Abstract

Plasmodium vivax is the most widespread human malaria parasite 1. The presence of extravascular reservoirs 2, the early circulation of infective stages (gametocytes), and relapsing infections arising from dormant liver stages 3 render this parasite particularly difficult to control and eliminate 4. Experimental research is limited by the lack of a continuous culture in vitro system that fulfills the parasites needs,5 namely its tropism for immature CD71+ red blood cells (RBCs). 5 Here, we report a humanized mice model, which upon engraftment of human hematopoietic progenitor and stem cells (HPSCs), exhibits efficient human erythropoiesis. Humanized HIS-HEry mice inoculated with cryopreserved P. vivax samples sustain long-lasting asexual parasite multiplication within CD71+ human RBCs and differentiation into mature gametocytes that can be efficiently transmitted to Anopheles mosquitoes, leading to formation salivary-gland sporozoites. Blood stages can be sequentially transferred to uninfected humanized mice by injection of fresh or frozen infected bone marrow cells, providing a unique murine model for the long-term maintenance of P. vivax isolates. This work offers a novel experimental platform to investigate the biology of RBC invasion and intraerythrocytic P. vivax development in vivo and evaluate new interventions against this elusive human parasite.