Abstract

BackgroundMalaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries. Among the five species of Plasmodium parasites that infect humans, Plasmodium falciparum accounts for the highest morbidity and mortality associated with malaria. Since humans are the only natural hosts for P. falciparum, the lack of convenient animal models has hindered the understanding of disease pathogenesis and prompted the need of testing anti-malarial drugs and vaccines directly in human trials. Humanized mice hosting human cells represent new pre-clinical models for infectious diseases that affect only humans. In this study, the ability of human-immune-system humanized HLA-DR4.RagKO.IL2RγcKO.NOD (DRAG) mice to sustain infection with P. falciparum was explored.MethodsFour week-old DRAG mice were infused with HLA-matched human haematopoietic stem cells (HSC) and examined for reconstitution of human liver cells and erythrocytes. Upon challenge with infectious P. falciparum sporozoites (NF54 strain) humanized DRAG mice were examined for liver stage infection, blood stage infection, and transmission to Anopheles stephensi mosquitoes.ResultsHumanized DRAG mice reconstituted human hepatocytes, Kupffer cells, liver endothelial cells, and erythrocytes. Upon intravenous challenge with P. falciparum sporozoites, DRAG mice sustained liver to blood stage infection (average 3–5 parasites/microlitre blood) and allowed transmission to An. stephensi mosquitoes. Infected DRAG mice elicited antibody and cellular responses to the blood stage parasites and self-cured the infection by day 45 post-challenge.ConclusionsDRAG mice represent the first human-immune-system humanized mouse model that sustains the complex vertebrate life cycle of P. falciparum without the need of exogenous injection of human hepatocytes/erythrocytes or P. falciparum parasite adaptation. The ability of DRAG mice to elicit specific human immune responses to P. falciparum parasites may help deciphering immune correlates of protection and to identify protective malaria antigens.

Highlights

  • Malaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries

  • DRAG mice reconstitute human hepatocytes, Kupffer cells, and liver endothelial cells The ability of human haematopoietic stem cells (HSC) (CD34+) to differentiate into non-haematopoietic cells such as hepatocytes, cardiomyocytes, and endothelial cells has become evident in human and animal studies [27]. It was investigated whether DRAG mice develop human hepatocytes by measuring plasma levels of human transferrin, a protein secreted by human hepatocytes [28]

  • The results indicated that HSC-infused DRAG mice develop human hepatocytes, Kupffer cells, and liver endothelial cells

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Summary

Introduction

Malaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries. Among the five species of Plasmodium parasites that infect humans, Plasmodium falciparum accounts for the highest morbidity and mortality associated with malaria. Since humans are the only natural hosts for P. falciparum, the lack of convenient animal models has hindered the understanding of disease pathogenesis and prompted the need of testing anti-malarial drugs and vaccines directly in human trials. Humanized mice hosting human cells represent new pre-clinical models for infectious diseases that affect only humans. Mature liver stage parasites are released to the bloodstream to invade red blood cells (RBCs) and to initiate the asexual erythrocytic cycles responsible for the clinical manifestations of malaria [1]. Among the five species of Plasmodium that infect humans, Plasmodium falciparum is the most virulent with 1.2 billion people at high risk. The current rise of earth temperature could hasten mosquito breeding at higher altitudes and latitudes and might increase the burden of malaria across the globe [3]

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