Patterns of resistance to <i>Candida albicans</i> in inbred mouse strains

Ashman, R. B.; Bolitho, Erin M.; Papadimitriou, J. M.

doi:10.1038/icb.1993.25

Cited by 58 publications

(50 citation statements)

References 10 publications

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“…Maximum linkage was found to the marker D2Mit295 (w 2 ¼ 79.4 (kidney) and 73.2 (brain); LOD ¼ 17.2 (kidney) and 15.9 (brain)), which maps to 17 cM on chromosome 2 ( Table 2). Since the gene for complement component 5 (C5/Hc) mapped less than 7 cM away from this marker 27 and had been previously implicated for its role in controlling response to candidiasis in inbred mouse strains, [28][29][30] we looked directly at this gene to determine if it was responsible for the linkage identified on this chromosome. A/J mice are deficient in C5 production, whereas B6 produce normal levels.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2005

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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 Â C57BL/6J] F 2 mice 48 h after infection with 5 Â 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-a 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. Genes and Immunity (2005) 6, 672-682.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2005

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“…Earlier studies in inbred mouse strains have documented the critical role of the C5 complement component, whose deficiency in the form of a naturally occurring 2-bp mutation (28), causes strong susceptibility to C. albicans infection (fungal proliferation, overall survival) (10,14,16,30,53). In addition, we and others have mapped Carg loci, namely Carg1 through Carg4, that additionally regulate susceptibility to C. albicans infection in a C5-independent fashion (29,32,33).…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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“…Over the years, the response of a number of different inbred strains to systemic candidiasis has been assessed, with fungal load and mortality being the two most commonly measured phenotypes (Table 2). 33,35,74,[106][107][108][109][110][111] For the more frequently tested strains, results between experiments are fairly consistent, despite differences in experimental conditions, such as C. albicans strain and dose used and the time of assessment of fungal load (fixed time point or at time of death). Interstrain differences are apparent with respect to susceptibility to infection with C. albicans, although correspondence between mortality and fungal burden is not always seen, suggesting the possibility of alternate genetic control for these traits.…”

Section: Studies In Inbred Mouse Strainsmentioning

confidence: 97%

Genetic analysis of innate immunity in resistance to Candida albicans

2004

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Systemic candidiasis is a significant cause of nosocomial infections and the mechanisms of defense against Candida albicans in humans remain poorly understood. Studies in animal models have demonstrated the importance of innate immunity in controlling the response to infection. Although Th1 cytokines have been shown to direct the overall outcome of infection, the precise role of the Th1/Th2 response and, more generally, the adaptive immune response as a whole, in systemic candidiasis, appears to apply mainly to the development of resistance to reinfection. A genetic approach to the identification of host factors regulating pathogenesis and susceptibility to C. albicans infection has been used in humans and in mouse models of infection. Mouse mutants bearing experimentally induced mutations in specific genes have provided a systematic tool for directly assessing the role of individual proteins in C. albicans susceptibility. Inbred mouse strains have been valuable in showcasing the spectrum of naturally occurring variations in initial susceptibility to infection, and type of disease developed. Crosses between resistant and susceptible strains have led to the detection of additional gene effects affecting innate immunity. Of particular interest is the major effect of a naturally occurring loss-of-function mutation in the C5 complement component that has become fixed in many inbred strains. These and other studies have shown that both a functional complement pathway and robust inflammatory response are critical for resistance to C. albicans.

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Patterns of resistance to Candida albicans in inbred mouse strains

Cited by 58 publications

References 10 publications

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

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

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

Genetic analysis of innate immunity in resistance to Candida albicans

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