Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain.
Malaria is a complex infectious disease in which the host/parasite interaction is strongly influenced by host genetic factors. The consequences of plasmodial infections range from asymptomatic to severe complications like the neurological syndrome cerebral malaria induced by Plasmodium falciparum in humans and Plasmodium berghei ANKA in rodents. Mice infected with P. berghei ANKA show marked differences in disease manifestation and either die from experimental cerebral malaria (ECM) or from hemolytic anemia caused by hyperparasitemia (HP). A majority of laboratory mouse strains so far investigated are susceptible to ECM; however, a number of wild-derived inbred strains show resistance. To evaluate the genetic basis of this difference, we crossed a uniquely ECM-resistant, wild-derived inbred strain (WLA) with an ECM susceptible laboratory strain (C57BL/6J). All of the (WLA x C57BL/6J) F(1) and 97% of the F(2) progeny displayed ECM resistance similar to the WLA strain. To screen for loci contributing to ECM resistance, we analyzed a cohort of mice backcrossed to the C57BL/6J parental strain. A genome wide screening of this cohort provided significant linkage of ECM resistance to marker loci in two genetic regions on chromosome 1 (chi(2) = 18.98, P = 1.3 x 10(-5)) and on chromosome 11 (chi(2) = 16.51, P = 4.8 x 10(-5)), being designated Berr1 and Berr2, respectively. These data provide the first evidence of loci associated with resistance to murine cerebral malaria, which may have important implications for the search for genetic factors controlling cerebral malaria in humans.
Unité Immunophysiopathologie Infectieuse, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1961, and Université Pierre et Marie Curie, 75005 Paris, France.
Sébastien
S
Bagot
Susana
S
Campino
Carlos
C
Penha-Gonçalves
Sylviane
S
Pied
Pierre-André
PA
Cazenave
Dan
D
Holmberg
D000818:Animals; D002874:Chromosome Mapping; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016779:Malaria, Cerebral / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics*; D010963:Plasmodium falciparum
D005819:Genetic Markers