title: Further improvements of the P. falciparum humanized mouse model.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Malaria Vaccine Development Laboratory, Institut Pasteur, Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Arnold
authors.forename: Rajeev Kumar
authors.initials: RK
authors.lastname: Tyagi
authors.forename: Pedro
authors.initials: P
authors.lastname: Meija
authors.forename: Claire
authors.initials: C
authors.lastname: Swetman
authors.forename: James
authors.initials: J
authors.lastname: Gleeson
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pérignon
authors.forename: Pierre
authors.initials: P
authors.lastname: Druilhe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004912:Erythrocytes / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007275:Injections, Intravenous; D007288:Inosine / Q000627:therapeutic use; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D007288:Inosine