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Pathogenesis of Candida albicans infections in the alternative chorio-allantoic membrane chicken embryo model resembles systemic murine infections.

Jacobsen ID, Grosse K, Berndt A, Hube B - PLoS ONE (2011)

Bottom Line: While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos.Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines.C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections.

View Article: PubMed Central - PubMed

Affiliation: Department for Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany. ilse.jacobsen@hki-jena.de

ABSTRACT
Alternative models of microbial infections are increasingly used to screen virulence determinants of pathogens. In this study, we investigated the pathogenesis of Candida albicans and C. glabrata infections in chicken embryos infected via the chorio-allantoic membrane (CAM) and analyzed the virulence of deletion mutants. The developing immune system of the host significantly influenced susceptibility: With increasing age, embryos became more resistant and mounted a more balanced immune response, characterized by lower induction of proinflammatory cytokines and increased transcription of regulatory cytokines, suggesting that immunopathology contributes to pathogenesis. While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos. IL-22 and IL-17A were only upregulated after the peak mortality in the chicken embryo model occurred; thus, the role of the Th17 response in this model remains unclear. Abscess formation occurs frequently in murine models, whereas the avian response was dominated by granuloma formation. Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines. However, fungal burden did not correlate with virulence and for few mutants like bcr1Δ and tec1Δ different outcomes in survival compared to murine infections were observed. C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections. These data suggest that the pathogenesis of C. albicans infections in the chicken embryo model resembles systemic murine infections but also differs in some aspects. Despite its limitations, it presents a useful alternative tool to pre-screen C. albicans strains to select strains for subsequent testing in murine models.

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Age-dependent mortality after application of 100 µg LPS on the CAM.Survival is shown as Kaplan-Meyer curve, n = 20 per group per experiment, two independent experiments. Significant mortality (compared to age-matched PBS control, log rank test) was only observed for embryos infected on developmental day (DD) 8 (P<0.001) and DD10 (P<0.01). The log rank test for trend was significant for comparison of LPS groups (P<0.005).
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pone-0019741-g002: Age-dependent mortality after application of 100 µg LPS on the CAM.Survival is shown as Kaplan-Meyer curve, n = 20 per group per experiment, two independent experiments. Significant mortality (compared to age-matched PBS control, log rank test) was only observed for embryos infected on developmental day (DD) 8 (P<0.001) and DD10 (P<0.01). The log rank test for trend was significant for comparison of LPS groups (P<0.005).

Mentions: In mice, systemic infection with C. albicans leads to progressive sepsis [10]. Using E. coli LPS applied onto the CAM, we confirmed previous observations by Smith and Thomas [25] that chicken embryos are susceptible to lethal septic shock and that this susceptibility is age-dependent (Fig. 2). Therefore, we hypothesized that an age-dependent sepsis-like response might contribute to the age-dependency of mortality in embryos infected with C. albicans. To test this hypothesis, we determined the transcription levels of cytokines, which have been implicated in pathogenesis in mice [11], [26], in the CAM of embryos challenged either with LPS or C. albicans. Cytokines function as mediators for immune cell recruitment, activation and immune modulation during infection and are involved in the development of sepsis [27].


Pathogenesis of Candida albicans infections in the alternative chorio-allantoic membrane chicken embryo model resembles systemic murine infections.

Jacobsen ID, Grosse K, Berndt A, Hube B - PLoS ONE (2011)

Age-dependent mortality after application of 100 µg LPS on the CAM.Survival is shown as Kaplan-Meyer curve, n = 20 per group per experiment, two independent experiments. Significant mortality (compared to age-matched PBS control, log rank test) was only observed for embryos infected on developmental day (DD) 8 (P<0.001) and DD10 (P<0.01). The log rank test for trend was significant for comparison of LPS groups (P<0.005).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094387&req=5

pone-0019741-g002: Age-dependent mortality after application of 100 µg LPS on the CAM.Survival is shown as Kaplan-Meyer curve, n = 20 per group per experiment, two independent experiments. Significant mortality (compared to age-matched PBS control, log rank test) was only observed for embryos infected on developmental day (DD) 8 (P<0.001) and DD10 (P<0.01). The log rank test for trend was significant for comparison of LPS groups (P<0.005).
Mentions: In mice, systemic infection with C. albicans leads to progressive sepsis [10]. Using E. coli LPS applied onto the CAM, we confirmed previous observations by Smith and Thomas [25] that chicken embryos are susceptible to lethal septic shock and that this susceptibility is age-dependent (Fig. 2). Therefore, we hypothesized that an age-dependent sepsis-like response might contribute to the age-dependency of mortality in embryos infected with C. albicans. To test this hypothesis, we determined the transcription levels of cytokines, which have been implicated in pathogenesis in mice [11], [26], in the CAM of embryos challenged either with LPS or C. albicans. Cytokines function as mediators for immune cell recruitment, activation and immune modulation during infection and are involved in the development of sepsis [27].

Bottom Line: While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos.Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines.C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections.

View Article: PubMed Central - PubMed

Affiliation: Department for Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany. ilse.jacobsen@hki-jena.de

ABSTRACT
Alternative models of microbial infections are increasingly used to screen virulence determinants of pathogens. In this study, we investigated the pathogenesis of Candida albicans and C. glabrata infections in chicken embryos infected via the chorio-allantoic membrane (CAM) and analyzed the virulence of deletion mutants. The developing immune system of the host significantly influenced susceptibility: With increasing age, embryos became more resistant and mounted a more balanced immune response, characterized by lower induction of proinflammatory cytokines and increased transcription of regulatory cytokines, suggesting that immunopathology contributes to pathogenesis. While many aspects of the chicken embryo response resembled murine infections, we also observed significant differences: In contrast to systemic infections in mice, IL-10 had a beneficial effect in chicken embryos. IL-22 and IL-17A were only upregulated after the peak mortality in the chicken embryo model occurred; thus, the role of the Th17 response in this model remains unclear. Abscess formation occurs frequently in murine models, whereas the avian response was dominated by granuloma formation. Pathogenicity of the majority of 15 tested C. albicans deletion strains was comparable to the virulence in mouse models and reduced virulence was associated with significantly lower transcription of proinflammatory cytokines. However, fungal burden did not correlate with virulence and for few mutants like bcr1Δ and tec1Δ different outcomes in survival compared to murine infections were observed. C. albicans strains locked in the yeast stage disseminated significantly more often from the CAM into the embryo, supporting the hypothesis that the yeast morphology is responsible for dissemination in systemic infections. These data suggest that the pathogenesis of C. albicans infections in the chicken embryo model resembles systemic murine infections but also differs in some aspects. Despite its limitations, it presents a useful alternative tool to pre-screen C. albicans strains to select strains for subsequent testing in murine models.

Show MeSH
Related in: MedlinePlus