Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection.
Cryptococcus neoformans is a major cause of fungal pneumonia, meningitis and disseminated disease in the immune compromised host. Here we have used a clinically relevant model to investigate the genetic determinants of susceptibility to progressive cryptococcal pneumonia in C57BL/6J and CBA/J inbred mice. At 5 weeks after infection, the lung fungal burden was over 1000-fold higher in C57BL/6J compared to CBA/J mice. A genome-wide scan performed on 210 male and 203 female (CBA/J x C57BL/6J) F2 progeny using lung colony-forming units as a quantitative trait revealed a sex difference in genetic architecture with three loci (designated Cnes1-Cnes3) associated with susceptibility to cryptococcal pneumonia. Single locus analysis identified significant loci on chromosomes 3 (Cnes1) and 17 (Cnes2) with logarithm of the odds (LOD) scores of 4.09 (P=0.0110) and 7.30 (P<0.0001) that explained 8.9 and 15.9% of the phenotypic variance, respectively, in female CBAB6F2 and one significant locus on chromosome 17 (Cnes3) with a LOD score of 4.04 (P=0.010) that explained 8.6% of the phenotypic variance in male CBAB6F2 mice. Genome-wide pair-wise analysis revealed significant quantitative trait locus interactions in both the female and male CBAB6F2 progeny that collectively explained 43.8 and 19.5% of phenotypic variance in each sex, respectively.
Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada.
S F
SF
Carroll
J C
JC
Loredo Osti
L
L
Guillot
K
K
Morgan
S T
ST
Qureshi
D000818:Animals; D003453:Cryptococcosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D003455:Cryptococcus neoformans / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D019655:Quantitative Trait, Heritable; D012727:Sex Characteristics