Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity

Abstract

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.

Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guérin) infection in wild-derived Mus spretus mice

“…This strategy has been used to map novel loci regulating complex traits such as susceptibility to infection with Salmonella typhimurium 15 and Plasmodium berghei. 16,17 In the present study, we show that despite presence of fixed Nramp1 G169 resistance allele, M. spretus (SPRET/EiJ) is quite susceptible to low dose infection with M. bovis (BCG). We have used informative crosses to map novel loci modulating Nramp1-mediated resistance to this infection.…”

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

“…For example, the resistance of F1 intercrossed BALB/c (resistant) and C57BL/6 (susceptible) mice to the development of ECM is determined by age, and environmental exposure, with young mice (8-10 weeks) susceptible to ECM and older mice (16-20 weeks) resistant to the development of cerebral signs (Hearn et al 2000). Genetic resistance to ECM and P. berghei ANKA infection has been mapped using intercrossed resistant and susceptible strains of mice to loci on chromosomes 1, 9, 11, 17 and 18 (Bagot et al 2002 ;Nagayasu et al 2002 ;Ohno and Nishimura, 2004 ;Campino et al 2005). However, the genes encoded within each of these regions that control resistance to ECM and parasite levels remain to be identified.…”

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

“…This method has been used to analyze similar data sets. 19 Data were also analyzed using the binary model, segregating mice into two categories based on survival past day 13. The cutoff used for genome-wide significance (Po0.05) was 4.19 for the two-part model and 3.50 for the binary model based on 1000 permutations.…”

“…17 Subsequently, QTLs designated Berr1 (chromosome 1), Berr2 (chromosome 11), Berr3 (chromosome 9) and Berr4 (suggestive linkage to chromosome 4) affecting the presence and severity of neurological symptoms following infection were mapped in F2 mice derived from C57BL/6 (susceptible) and the resistant wild-derived WLA strain. 18,19 Finally, the Cmsc locus mapping to the H-2 region of chromosome 17 was found to affect susceptibility in progeny of CBA mice crossed with the resistant DBA/2 strain. 20 In all cases, the detected QTLs span large chromosomal segments, and the causative genes underlying their effect on survival time in P. berghei-infected animals have not been identified.…”