Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

Tuite, Ashleigh R.; Elias, Miria; Picard, Serge; Mullick, Alaka; Gros, Philippe

doi:10.1038/sj.gene.6364254

Cited by 56 publications

(58 citation statements)

References 42 publications

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“…41 Inbred mice have demonstrated clear variation in heritable susceptibility to various routes of infection with C. neoformans, yet the identification of genetic loci that mediate host resistance has not been fully elucidated. 12,28 Utilizing a direct intratracheal method for administration of C. neoformans 24067 that models human infection, we have confirmed the divergent host response of the C57BL/6J and CBA/J inbred strains and have used this as a basis for genomewide analysis of QTLs that influence lung fungal burden in a large population of segregating CBAB6F2 animals.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

et al. 2008

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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 Â 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 ¼ 0.0110) and 7.30 (Po0.0001) 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 ¼ 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.

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Section: Discussionmentioning

confidence: 99%

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

et al. 2008

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“…In this latter case, the H2 locus was sufficient to explain the entire difference in fungal burden between the parental strains. Our previous data distinguished loci influencing histoplasmosis from those affecting other pathogens, such as the influence of the mouse C5 gene on Candida infection (9). The further refinement here of our earlier mapping data to H2 itself enabled an analysis of the immunological basis for differential histoplasmosis outcomes.…”

Section: Resultsmentioning

confidence: 94%

Genetic control of immune cell types in fungal disease

Mayfield

Fontana

Rine

2010

Proc. Natl. Acad. Sci. U.S.A.

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Millions of people harbor latent infections of the fungus Histoplasma capsulatum. Such persistent infections represent a stalemate between mechanisms of virulence and the immune response. The differing responses of inbred mouse strains to the same pathogen reflect variation in the genes that control the outcome of infection. Here we show that a 250-fold difference in H. capsulatum susceptibility between inbred mouse strains is attributable to the genotype at the MHC H2 locus. Gene expression analysis of strains varying only at the H2 locus identified genotype-specific and genotype-independent expression signatures, including infection-induced genes such as the fungal pattern recognition receptor Clec7a. Surprisingly, B-cell-specific gene expression was negatively correlated with fungal burden, whereas neutrophil-specific genes were correlated with superior disease outcome. Indeed, disease outcome improved when B cells were eliminated and neutrophils were more active, a previously unknown aspect of the host response. These data refine the understanding of genetic influences on histoplasmosis, reveal how shifts in the composition of immune cell populations compel different disease outcomes, and uncover how innate immunity modulation alters histoplasmosis.G enetic differences among individuals can have profound effects on infectious disease susceptibility and severity; for example, severe infections with the dimorphic fungal pathogen Coccidioides immitis are more frequent in males and people of African or Asian descent (1). This relationship inspires the hope that uncovering the pivotal genes affecting disease outcome might lead to new therapeutic strategies for controlling disease. For histoplasmosis, a fungal pneumonia affecting millions of people worldwide (2), infection outcomes vary greatly among mouse strains with only minor differences in cytokine profiles (3, 4). Although molecular ablation has connected an orderly and well-defined cytokine response to histoplasmosis outcome (5-7), previous mouse strain studies have highlighted the unexplained aspects of a successful immune response. The experiments reported herein identify a major influence of the H2 locus on experimental infections of mice with the fungal pathogen Histoplasma capsulatum, uncover gene expression signatures of neutrophils and B cells in resistant strains of mice, show that B cells impair the antifungal response, and implicate the innate immune system as an early control point. ResultsGenetic Control of Disease Outcome After H. capsulatum Infection.We previously mapped quantitative trait loci controlling the phenotype of fungal burden using recombinant inbred mice (3). These data identify two regions on chromosome 17 linked to 250-fold lower fungal burden in the spleens of resistant A/J mice compared with sensitive C57BL/6 (B6) mice. One of those regions is tightly linked to the MHC H2, a highly variable multigene complex encoding the proteins responsible for antigen presentation. To test the contribution of the H2 locus to the immune respon...

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“…In addition to the major effect of the C5 status on fungal replication in target organs (kidney, brain) and overall survival from C. albicans infection (10), early studies in AcB/BcA recombinant congenic mouse strains suggested that additional C5-unrelated genetic loci could also contribute to host response to C. albicans infection (10,30,31). Other studies by Ashman et al (32,33) suggested that severity of infection evaluated by type and extent of histopathologic damage in target organs is regulated by other loci (Carg1, Carg2), whose map location and identity have remained unknown.…”

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confidence: 99%

“…We have previously shown that roughly half of the inbred laboratory mouse strains carry a naturally occurring 2-bp deletion in the C5 gene (Hc allele) that causes C5 deficiency (28), which renders the affected strains susceptible to acute infection with C. albicans (10,16,29). In addition to the major effect of the C5 status on fungal replication in target organs (kidney, brain) and overall survival from C. albicans infection (10), early studies in AcB/BcA recombinant congenic mouse strains suggested that additional C5-unrelated genetic loci could also contribute to host response to C. albicans infection (10,30,31).…”

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confidence: 99%

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

Radovanovic

Leung

Iliescu

et al. 2014

The Journal of Immunology

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In the immunocompromised host, invasive infection with the fungal pathogen Candida albicans is associated with high morbidity and mortality. Sporadic cases in otherwise normal individuals are rare, and they are thought to be associated with genetic predisposition. Using a mouse model of systemic infection with C. albicans, we identified the SM/J mouse strain as unusually susceptible to infection. Genetic linkage studies in informative [C57BL/6JxSM/J]F2 mice identified a major locus on distal chromosome 15, given the appellation Carg5, that regulates C. albicans replication in SM/J mice. Cellular and molecular immunophenotyping experiments, as well as functional studies in purified cell populations from SM/J and C57BL/6J, and in [C57BL/6JxSM/J]F2 mice fixed for homozygous or heterozygous Carg5 alleles, indicate that Carg5-regulated susceptibility in SM/J is associated with a complex defect in the myeloid compartment of these mice. SM/J neutrophils express lower levels of Ly6G, and importantly, they show significantly reduced production of reactive oxygen species in response to stimulation with fMLF and PMA. Likewise, CD11b+Ly6G−Ly6Chi inflammatory monocytes were present at lower levels in the blood of infected SM/J, recruited less efficiently at the site of infection, and displayed blunted oxidative burst. Studies in F2 mice establish strong correlations between Carg5 alleles, Ly6G expression, production of serum CCL2 (MCP-1), and susceptibility to C. albicans. Genomic DNA sequencing of chromatin immunoprecipitated for myeloid proinflammatory transcription factors IRF1, IRF8, STAT1 and NF-κB, as well as RNA sequencing, were used to develop a “myeloid inflammatory score” and systematically analyze and prioritize potential candidate genes in the Carg5 interval.

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Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

Cited by 56 publications

References 42 publications

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

Genetic control of immune cell types in fungal disease

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

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