title: A humanized mouse model for sequestration of Plasmodium falciparum sexual stages and in vivo evaluation of gametocytidal drugs.
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.
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'excellence GR-Ex, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Duffier
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'excellence GR-Ex, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lorthiois
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Cisteró
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'excellence GR-Ex, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Dupuy
authors.affiliation: Human Histopathology and Animal Models, Institut Pasteur, Paris, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Human Histopathology and Animal Models, Institut Pasteur, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.affiliation: 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.|AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, F-75013, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mayor
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'excellence GR-Ex, Paris, France.|Genetics and Genomics of Insect Vectors Unit, Institut Pasteur, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lavazec
authors.affiliation: 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.|AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie, Paris, France.
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno Sabater
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000469:parasitology; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D007274:Injections, Intraperitoneal; D008018:Life Cycle Stages / Q000187:drug effects*; D016778:Malaria, Falciparum / Q000469:parasitology*; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development*; D011319:Primaquine / Q000008:administration & dosage* / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000469:parasitology
chemical_list: D000962:Antimalarials; D011319:Primaquine