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Sci Rep. 2016 Oct 12;6:35025. doi: 10.1038/srep35025.

A humanized mouse model for sequestration of Plasmodium falciparum sexual stages and in vivo evaluation of gametocytidal drugs.

Author information

1
Inserm U1016, Institut Cochin, Paris, France.
2
Cnrs, UMR8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Laboratoire d'excellence GR-Ex, Paris, France.
5
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
6
Human Histopathology and Animal Models, Institut Pasteur, Paris, France.
7
Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital, F-75013, Paris, France.
8
AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, F-75013, Paris, France.
9
Genetics and Genomics of Insect Vectors Unit, Institut Pasteur, Paris, France.
10
AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie, Paris, France.

Abstract

The development of new drugs to disrupt malaria transmission requires the establishment of an in vivo model to address the biology of Plasmodium falciparum sexual stages (gametocytes). Herein we show that chemically immune-modulated NSG mice grafted with human erythrocytes support complete sexual development of P. falciparum parasites and generate high gametocytemia. Immunohistochemistry and RT-qPCR analyses indicate an enrichment of immature gametocytes in the bone marrow and the spleen, suggesting a sequestration mechanism reminiscent to that observed in humans. Upon primaquine treatment, elimination of gametocytes from peripheral blood and from sequestration sites was observed, providing a proof of concept that these mice can be used for testing drugs. Therefore, this model allows the investigation of P. falciparum sexual commitment, gametocyte interactions with the bone marrow and spleen and provides the missing link between current in vitro assays and Phase I trials in humans for testing new malaria gametocytidal drugs.

PMID:
27731362
PMCID:
PMC5059736
DOI:
10.1038/srep35025
[Indexed for MEDLINE]
Free PMC Article

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