Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain

Abstract

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.

Figure 1

Genetic resistance to ECM after infection with P. berghei ANKA clone 1.49L is a dominant trait. After infection, the mice that died between days 5 and 12 developed a neurological syndrome, and were designated ECM susceptible (ECMS). The remaining animals resist ECM but died at a later stage with HP and hemolytic anemia, being designated HP susceptible (HPS). In the F₂ progeny, some individuals were found to resist to both ECM and HP. We tested 49 females and 15 males C57BL/6J, 11 females and 10 males WLA, 13 females and 18 males (WLA × C57BL/6J) F₁, 99 females and 91 males (WLA × C57BL/6J) F₁ × C57BL/6J and 79 females and 96 males (WLA × C57BL/6J) F₂.

Figure 2

Analysis of the association between ECM resistance and markers on chromosome 1. Markers shown were use to genotype 190 backcross mice. χ² tests of association (1 degree of freedom) were performed for the indicate markers and the obtain χ² and P values are shown. Marker orders and absolute positions along the chromosomes were based on the mouse genome database (www.jax.org) and are indicated (in cM).

Figure 3

Analysis of the association between ECM resistance and markers on chromosome 11. The results are present as described in Fig. 2.