Humanized Mouse Models for the Study of Human Malaria Parasite Biology, Pathogenesis, and Immunity

Abstract

Malaria parasite infection continues to inflict extensive morbidity and mortality in resource-poor countries. The insufficiently understood parasite biology, continuously evolving drug resistance and the lack of an effective vaccine necessitate intensive research on human malaria parasites that can inform the development of new intervention tools. Humanized mouse models have been greatly improved over the last decade and enable the direct study of human malaria parasites in vivo in the laboratory. Nevertheless, no small animal model developed so far is capable of maintaining the complete life cycle of Plasmodium parasites that infect humans. The ultimate goal is to develop humanized mouse systems in which a Plasmodium infection closely reproduces all stages of a parasite infection in humans, including pre-erythrocytic infection, blood stage infection and its associated pathology, transmission as well as the human immune response to infection. Here, we discuss current humanized mouse models and the future directions that should be taken to develop next-generation models for human malaria parasite research.

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

“…Methods used to conduct these assays were recently described [20]. An alternative model has also been reported in which mice have been engineered to contain human hepatocytes which allows infection by P. falciparum sporozoites [21,22].…”

Developing a xenograft model of human vasculature in the mouse ear pinna

“…Although this imaging work is preliminary, the model holds great potential in further assessing the behaviours of parasites, including P. falciparum, trypanosomes and schistosomes, as well as bacterial infections such as Neisseria meningitidis, which are all known to mediate effects in both the skin and adipose tissue in patients 13,43 . Aside from infection research, the model could also be further adapted to include components of a human immune system, either through the transfer of peripheral blood mononuclear cells (PBMCs) or the transplantation of haematopoietic stem cells, which is a feature often incorporated into humanised models 44 . This would allow us to visualise various aspects of immune cell behaviours, including extravasation, in real time using acute models of inflammation.…”

Quantitative intravital imaging ofPlasmodium falciparumsporozoites: A novel platform to test malaria intervention strategies

“…In vitro assays quantifying cell traversal and invasion suffer from the low infectivity of P. falciparum sporozoites in vitro and our lack of knowledge on how to activate P. falciparum sporozoites for these processes once they have been dissected from mosquito salivary glands. Significant progress was made with the development of a humanized mouse model (33), however, the mice used for these assays are expensive and immune-compromised, making it difficult to evaluate vaccine candidates using this model. Our model, using immune-competent mice, enables the use of large numbers of mice due to their low-cost relative to the humanized mice, and evaluation of vaccine candidates due to their fully competent immune system.…”