Characterization of Plasmodium falciparum and Plasmodium vivax Liver Stage Development in Novel Human Liver Chimeric Mice

Abstract

Malaria is one of the world’s leading causes of death, killing over 550,000 people in 2013 alone. The disease is caused by the Plasmodium parasite, which is transmitted through the female Anopheles mosquitoes to humans. Five strains infect humans, of which two – Plasmodium falciparum and Plasmodium vivax, are the most deadly and widespread, respectively. The limited host range of the Plasmodium species that causes malaria in humans poses challenges for studying these parasites in experimentally tractable in vivo systems. To address this challenge, human liver chimeric mice have been developed to study the poorly understood liver stage development of human malaria. Four novel xenorecipient strains developed by the Ploss lab were characterized via weight, survival, and albumin levels for their ability to support human liver grafts. Highly engrafted mice were challenged with cryopreserved recombinant P. falciparum sporozoites. While in vivo imaging showed robust parasitemia in mice, qPCR and immunofluorescence failed to detect any level of P. falciparum infection. Further experiments using laser capture microdissection and RNAseq will be used to determine transcriptomic profiles of P. falciparum liver development stages. Use of DiR lipophilic dye as a sporozoite membrane marker is currently being explored to allow the use of fresh P. falciparum sporozoites for infection. Groundwork for P. vivax challenge experiments in Peru has been established and infection experiments will follow shortly. The development of human liver 7 chimeric mice provides a unique opportunity to study human diseases in a small animal model, which can then be used for preclinical drug assessment.