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Updated: Jun 2, 2026
Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells
Published on: August 29, 2016
Further improvements of the P. falciparum humanized mouse model
Ludovic Arnold1, Rajeev Kumar Tyagi, Pedro Meija
1Malaria Vaccine Development Laboratory, Institut Pasteur, Paris, France.
Background:
It has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines.
Materials/Methods:
We investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2Rγ deficiency (NSG mice).
Results:
We demonstrate here the role of aging, of inosine and of the IL-2 receptor γ mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent.
Conclusion:
The combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.
Insights
A new malaria model using NSG mice, clodronate liposomes, and IV delivery of human red blood cells improves reproducibility and relevance for studying Plasmodium falciparum infection and testing new antimalarials.
Area of Science:
- Immunology
- Infectious Diseases
- Parasitology
Background:
- Previous models for studying Plasmodium falciparum in mice had limited reproducibility due to inflammation.
- Optimizing these models is crucial for developing new antimalarial drugs, combinations, and vaccines.
Purpose of the Study:
- To improve the reliability and relevance of mouse models for Plasmodium falciparum research.
- To investigate methods for controlling innate immune responses and enhancing parasite growth.
Main Methods:
- Utilized intravenous (IV) delivery for human erythrocytes (huRBC) and P. falciparum.
- Employed immunodeficient NSG mice (IL-2Rγ deficient).
- Administered clodronate-loaded liposomes (clo-lip) to control innate defenses.
Main Results:
- Achieved 100% infection success rate in clo-lip treated NSG mice with IV delivery.
- Observed rapid, high-level, and long-lasting parasitemia, closely mimicking human malaria.
- Demonstrated model's suitability for various P. falciparum strains without adaptation, showing synchronization and partial sequestration.
Conclusions:
- The combination of NSG mice, clodronate liposomes, and IV delivery creates a reliable and relevant model for malaria research.
- This optimized model enhances the study of P. falciparum and the evaluation of novel therapeutics.
