Abstract
Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43×10−11) and a novel effect on distal chromosome 11 (P value = 7.63×10−9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNγ. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner.
Highlights
Candida albicans is an opportunistic fungal pathogen that exists commensally in the gastrointestinal and genitourinary tracts of healthy individuals[1], but that causes severe disseminated and often lethal infections in immunocompromised patients, such as those suffering from HIV infection or undergoing cancer chemotherapy[2]
Response to C. albicans infection in inbred mouse strains To identify novel component 5 (C5)-independent genetic effects regulating the proliferation of C. albicans organisms in target organs during disseminated infection, we surveyed 23 strains from the panel of 36 commonly used inbred mouse strains represented in the Jackson Mouse Phenome Database
AKR/J mice are C5-deficient [28], yet they showed mean log10CFU counts at 3.960.4 similar to that seen in the resistant B6 strain, and clearly distinct from that seen in the C5-deficient strains group
Summary
Candida albicans is an opportunistic fungal pathogen that exists commensally in the gastrointestinal and genitourinary tracts of healthy individuals[1], but that causes severe disseminated and often lethal infections in immunocompromised patients, such as those suffering from HIV infection or undergoing cancer chemotherapy[2]. In the United States alone, Candida species constitute the fourth most common causative agent of nosocomial bloodstream infections, and are associated with significant attributable mortality in both adults and children (47% vs 29%)[3,4,5]. Genetic predisposition to disseminated candidiasis in non-immunocompromised humans has not yet been associated to any particular gene, individuals presenting impaired phagocyte function are more susceptible to Candida infections[10], as observed in myeloperoxidase (MPO) deficiency. Deleterious mutations in multiple direct or downstream immune effectors, notably CLEC7A[11], STAT3[12], and CARD9[13], have been found in human cohorts with high prevalence of chronic mucocutaneous candidiasis (CMC) and have been recapitulated and studied in mice
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