FULL PAPER Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity S Campino 1,2,4 , S Bagot 3,4 , M-L Bergman 1,2 , P Almeida 1 , N Sepu ´ lveda 1 , S Pied 1,3 , C Penha-Gonc ¸alves 1 , D Holmberg 1,2 and P-A Cazenave 3 1 Instituto Gulbenkian de Cie ˆncia, Oeiras, Portugal; 2 Medical and Clinical Genetics, Umea ˚ University, Umea ˚, Sweden; 3 Unite ´ d’Immunophysiopathologie Infectieuse, De ´partement d’Immunologie, Institut Pasteur, Paris, France Unprecedented cure after infection with the lethal Plasmodium berghei ANKA was observed in an F2 progeny generated by intercrossing the wild-derived WLA and the laboratory C57BL/6 mouse strains. Resistant mice were able to clear parasitaemia and establish immunity. The observed resistance was disclosed as a combinatorial effect of genetic factors derived from the two parental strains. Genetic mapping of survival time showed that the WLA allele at a locus on chromosome 1 (colocalizing with Berghei resistance 1 (Berr1), a locus associated with resistance to experimental cerebral malaria) increases the probability to resist early death. Also, the C57Bl/6 allele at a novel locus on chromosome 9 (Berr3) confers overall resistance to this lethal Plasmodium infection. This report underlines the value of using wild-derived mouse strains to identify novel genetic factors in the aetiology of disease phenotypes, and provides a unique model for studying parasite clearance and immunity associated with malaria. Genes and Immunity (2005) 6, 416–421. doi:10.1038/sj.gene.6364219; published online 23 June 2005 Keywords: Plasmodium berghei; experimental cerebral malaria; hyperparasitaemia; inbred wild-derived mouse strains; quantitative trait loci; nonparametric analysis Introduction Malaria is a major world-scale health problem being responsible for 1–2 million deaths every year, mainly in tropical Africa where it is endemic. Plasmodium falci- parum is the leading cause of death and is responsible for the more severe forms of the disease, including the neurological syndrome cerebral malaria (CM). Efforts to find an effective way to control the disease have been thwarted by the emergence of parasite resistance to the commonly used drugs and by mosquito resistance to insecticides. Given the high impact of malaria as a public health problem, new targets for therapeutic intervention are fundamental. The understanding of the natural mechanisms of host defense against the disease could point out novel intervention targets. The influence of the host genetic background on malaria has been verified in several studies, both in humans and in murine models. Epidemiological studies and genetic linkage analyses in endemic areas have underscored the importance of the host genetic compo- nent against the disease. 1–3 The influence of genetic background on disease outcome is equally well estab- lished in murine models. This difference in susceptibility to malaria infection between mouse strains has prompted genetic studies in informative backcross and F2 progenies, as well as in recombinant inbred and congenic strains. These studies have confirmed that genetic susceptibility to malaria is indeed complex and have resulted in the mapping of several loci associated with susceptibility to P. chabaudi (Char1–8), 4–9 P. yoelii (Pmyr) 10 and P. berghei. 11 Furthermore, we recently identified two novel loci (Berghei resistance 1 and 2 (Berr1 and 2)) associated with resistance to experimental cerebral malaria (ECM) induced by P. berghei ANKA. 12 To further analyse the genetic basis for the control of resistance to P. berghei ANKA, we exploited the natural genetic diversity provided by inbred wild-derived mouse strains, and studied the segregation of malaria- related phenotypes in a (WLA  C57BL/6J)F2 cross. A novel phenotype, characterized by spontaneous cure to malaria infection induced by the otherwise lethal P. berghei ANKA, was identified in this F2 progeny representing the first description of mice capable of survival and cure from this Plasmodium infection. The segregation analysis of the F2 cohort revealed three major loci on chromosomes 1, 4 and 9 that control the survival time and parasitaemia kinetics during P. berghei ANKA infection. Received 1 November 2004; revised and accepted 23 March 2005; published online 23 June 2005 Correspondence: Proffesor P-A Cazenave, Unite ´ d’immunophysiopathologie Infectieuse, De ´partement d’Immunologie, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France. E-mail: cazenave@pasteur.fr or scampino@igc.gulbenkian.pt 4 Both these authors contributed equally to this work. Genes and Immunity (2005) 6, 416–421 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene