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Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain
Sébastien Bagot1, Susana Campino, Carlos Penha-Gonçalves
1Unité Immunophysiopathologie Infectieuse, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1961, and Université Pierre et Marie Curie, 75005 Paris, France.
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.
Insights
Genetic factors influence malaria severity. Researchers identified two key genetic regions, Berr1 and Berr2, linked to resistance against experimental cerebral malaria (ECM) in mice, offering insights into human malaria genetics.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Malaria pathogenesis is significantly shaped by host genetic factors, leading to varied outcomes from asymptomatic infection to severe cerebral malaria (ECM).
- While most laboratory mouse strains are susceptible to ECM, some wild-derived strains exhibit resistance, indicating a genetic basis for this difference.
Purpose of the Study:
- To investigate the genetic underpinnings of resistance to experimental cerebral malaria (ECM) using a cross between resistant wild-derived and susceptible laboratory mouse strains.
- To identify specific genetic loci associated with ECM resistance.
Main Methods:
- Crossed an ECM-resistant wild-derived inbred strain (WLA) with an ECM-susceptible laboratory strain (C57BL/6J).
- Analyzed F(1), F(2), and backcrossed progeny for ECM resistance phenotypes.
- Conducted genome-wide screening to identify linkage between resistance and genetic markers.
Main Results:
- F(1) and F(2) progeny predominantly inherited ECM resistance from the WLA parent.
- Genome-wide analysis revealed significant linkage of ECM resistance to two loci on chromosomes 1 (Berr1) and 11 (Berr2).
- These findings represent the first identification of loci associated with murine cerebral malaria resistance.
Conclusions:
- The study identifies specific genetic loci (Berr1 and Berr2) conferring resistance to experimental cerebral malaria in mice.
- These findings provide crucial insights into the genetic control of malaria, with potential implications for understanding and treating cerebral malaria in humans.