Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Feb;13(2):155-63.
doi: 10.1038/gene.2011.67. Epub 2011 Oct 6.

Genetic control of susceptibility to infection with Plasmodium chabaudi chabaudi AS in inbred mouse strains

A Laroque  1 , G Min-Oo, M Tam, I Radovanovic, M M Stevenson, P Gros
Affiliations

Genetic control of susceptibility to infection with Plasmodium chabaudi chabaudi AS in inbred mouse strains

A Laroque et al. Genes Immun. 2012 Feb.

Abstract

To identify genetic effects modulating the blood stage replication of the malarial parasite, we phenotyped a group of 25 inbred mouse strains for susceptibility to Plasmodium chabaudi chabaudi AS infection (peak parasitemia, survival). A broad spectrum of responses was observed, with strains such as C57BL/6J being the most resistant (low parasitemia, 100% survival) and strains such as NZW/LacJ and C3HeB/FeJ being extremely susceptible (very high parasitemia and uniform lethality). A number of strains showed intermediate phenotypes and gender-specific effects, suggestive of rich genetic diversity in response to malaria in inbred strains. An F2 progeny was generated from SM/J (susceptible) and C57BL/6J (resistant) parental strains, and was phenotyped for susceptibility to P. chabaudi chabaudi AS. A whole-genome scan in these animals identified the Char1 locus (LOD=7.40) on chromosome 9 as a key regulator of parasite density and pointed to a conserved 0.4-Mb haplotype at Char1 that segregates with susceptibility/resistance to infection. In addition, a second locus was detected in [SM/J × C57BL/6J] F2 mice on the X chromosome (LOD=4.26), which was given the temporary designation Char11. These studies identify a conserved role of Char1 in regulating response to malaria in inbred mouse strains, and provide a prioritized 0.4-Mb interval for the search of positional candidates.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Differential susceptibility of C57BL/6J and SM/J mice to P. chabaudi chabaudi AS infection
Mice were infected i.v. with 105 parasitized RBC, and daily parasitemia (expressed as percentage of parasitized RBC) and survival were recorded. (A) Course of infection (blood parasitemia) in C57BL/6J and SM/J mice over a 21 day period. (B) Peak parasitemia levels are shown for strain C57BL/6J and SM/J. Each circle represents one mouse. Statistical significance (two-tailed Student’s t-test; compared to B6) is indicated by stars: ***P<0.0001. (C) Kaplan-Meier survival curve. SM/J is represented by a dashed line and C57BL/6J by a solid line. Survival curves were compared by a Log-rank test and the median survival of SM/J was found to be significantly different from C57BL/6J (P=0.0035).
Figure 2
Figure 2. Segregation analysis of susceptibility to P. chabaudi chabaudi AS infection in [SM/J x C57BL/6J]F1 and F2 mice
17 F1 and 201 F2 animals as well as parental controls were infected i.v. with 105 parasitized RBC, and daily parasitemia (expressed as percentage of parasitized RBC) as well as survival from infection were recorded. (A) Kaplan-Meier survival curve. Survival curves were compared by a Log-rank test and the median survival of SM/J was found to be significantly different from C57BL/6J (P<0.0001). (B) The peak of parasitemia is shown separately for males and females. Each circle represents one mouse. Statistical significance between F2 males and females (two-tailed Mann-Whitney test) is indicated by stars: ***P<0.0001. (C) Distribution of peak parasitemia in the entire F2 population after regression of peak parasitemia levels to a gender-specific mean.
Figure 3
Figure 3. Genetic analysis of differential susceptibility to P. chabaudi chabaudi AS infection in resistant C57BL/6J and susceptible SM/J mice
Whole-genome analysis was carried out in 201 [SMxC57BL/6]F2 mice infected i.v. with 105 parasitized RBC, using sex corrected peak parasitemia as a quantitative trait. Interval mapping was done using the R/qtl software package. (A) Results for all chromosomes are plotted. Significance thresholds revealed by permutation testing (1000 permutations for autosomes and 14297 permutations for the X chromosome) are indicated. (B) Enhanced view of chromosome 9 and X. Vertical lines and hatched area delimit the 1.5-LOD support interval. (C) Effect of Char1 and Char11 alleles (at peak marker) on peak parasitemia. Males and females are plotted separately in order to reveal any potential sex effect. A and B correspond to SM/J and C57BL/6J alleles respectively.
Figure 4
Figure 4. Co-segregation of Char1 haplotypes in 129x1/SvJ, C57BL/6J, SM/J, SJL/J, C3H/HeJ and NC/Jic inbred strains
The position of the unique bi-allelic haplotype block common to C57BL/6J and 129/SvJ (resistant strains) but different from SM/J, SJL, C3H/He and NC/Jic (susceptible strains) is shown. SNP-based genotypes for C57BL/6J, 129/SvJ, SM/J, SJL/J and C3H/HeJ were obtained from the Mouse Hapmap project. The genotype of NC/Jic for the indicated SNPs was determined by genomic DNA sequencing. C57BL/6J alleles are depicted in grey. Alleles different from C57BL/6J alleles are depicted in black. Inbred strains were segregated into susceptible (S) and resistant (R) strains.
See this image and copyright information in PMC

References

    1. Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, et al. Malaria: progress, perils, and prospects for eradication. J Clin Invest. 2008;118(4):1266–1276. - PMC - PubMed
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361(5):455–467. - PMC - PubMed
    1. Corbel V, N’Guessan R, Brengues C, Chandre F, Djogbenou L, Martin T, et al. Multiple insecticide resistance mechanisms in Anopheles gambiae and Culex quinquefasciatus from Benin, West Africa. Acta Trop. 2007;101(3):207–216. - PubMed
    1. Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005;77(2):171–192. - PMC - PubMed
    1. Bongfen SE, Laroque A, Berghout J, Gros P. Genetic and genomic analyses of host-pathogen interactions in malaria. Trends Parasitol. 2009;25(9):417–422. - PubMed

Publication types