Genetic control of susceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice.
The importance of host factors in determining susceptibility to systemic Candida albicans infections is evident in both humans and mice. We have used a mouse model to study the genetic basis of susceptibility, using the inbred strains A/J and C57BL/6J, which are susceptible and resistant, respectively, based on different parameters of the response to infection. To identify genes responsible for this differential host response, brain and kidney fungal load were measured in 128 [A/J x C57BL/6J] F(2) mice 48 h after infection with 5 x 10(4) C. albicans blastospores. Segregation analysis in this informative population identified complement component 5 (C5/Hc) as the major gene responsible for this differential susceptibility (LOD of 22.7 for kidney, 19.0 for brain), with a naturally occurring mutation that causes C5 deficiency leading to enhanced susceptibility. C5 was also found to control heart fungal load, survival time, and serum TNF-alpha levels during infection. Investigation of the response to C. albicans challenge in a series of AcB/BcA recombinant congenic strains validated the importance of C5 in determining the host response. However, the strains BcA67 and BcA72 showed discordant phenotypes with respect to their C5 status, suggesting additional complexity in the genetic control of the inter-strain difference in susceptibility observed in A/J and C57BL/6J following systemic infection with C. albicans.
Tuite
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Department of Biochemistry, Center for the Study of Host Resistance, McGill University, 3655 Promenade Sir William Osler, Rm. 907, Montreal, Quebec, Canada H3G 1Y6.
Elias
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Picard
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Mullick
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Gros
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D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000382:microbiology; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D016009:Chi-Square Distribution; D002874:Chromosome Mapping; D002875:Chromosomes; D003182:Complement C5 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D008040:Genetic Linkage; D005819:Genetic Markers; D007668:Kidney / Q000382:microbiology; D008126:Lod Score; D051379:Mice; D020297:Mice, Congenic; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D003182:Complement C5; D005819:Genetic Markers; D014409:Tumor Necrosis Factor-alpha