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Avirulence of Candida albicans CaHK1 mutants in a murine model of hematogenously disseminated candidiasis.

ABSTRACT: Deletion of both alleles of the Candida albicans CaHK1 gene, which causes cells to flocculate when grown at pH 7.5, a pH comparable to that of mammalian blood, abolishes the ability of the yeast to establish a successful infection in a murine model of hematogenously disseminated candidiasis. Within 72 h all mice inoculated with the parental C. albicans strain had died. The mice infected with either the heterozygote or revertant strain, either of which harbors only one functional CaHK1 allele, also succumbed to the infection, although survivors were observed for up to 16 days postinfection. However, mice inoculated with the Deltacahk1 null strain survived for the course of the infection. These results indicate that CaHK1 is required for the virulence of C. albicans in a murine model of hematogenously disseminated candidiasis. In contrast, CaHK1 is not required for the virulence of C. albicans in a rat model of vaginal candidiasis.

SUBMITTER: Calera JA

PROVIDER: S-EPMC96739 | biostudies-literature | 1999 Aug

REPOSITORIES: biostudies-literature

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Avirulence of Candida albicans CaHK1 mutants in a murine model of hematogenously disseminated candidiasis.

Calera J A JA Zhao X J XJ De Bernardis F F Sheridan M M Calderone R R

Infection and immunity 19990801 8

Deletion of both alleles of the Candida albicans CaHK1 gene, which causes cells to flocculate when grown at pH 7.5, a pH comparable to that of mammalian blood, abolishes the ability of the yeast to establish a successful infection in a murine model of hematogenously disseminated candidiasis. Within 72 h all mice inoculated with the parental C. albicans strain had died. The mice infected with either the heterozygote or revertant strain, either of which harbors only one functional CaHK1 allele, al ...[more]

PMID: 10417206

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Project description:Pharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively for Candida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole. Isavuconazole pharmacokinetics were linear over the dose range studied. Oral-gastric doses of 640, 160, 40, and 10 mg of prodrug/kg of body weight produced peak levels of 0.51 to 25.4 mg/liter, an elimination half-life of 1 to 5 h, and an AUC from 0 h to infinity (AUC0-∞) of 0.9 to 287 mg · h/liter. The AUC/MIC ratio was the pharmacodynamic index that correlated best with efficacy (R(2), 0.84). Pharmacodynamic target studies were performed using 4 C. albicans isolates with both a 24-h and a 96-h treatment duration. The strains were chosen to include previously characterized fluconazole-resistant strains. The mean 50% effective doses (ED50) (expressed in mg/kg of body weight/12 h) and associated 24-h free-drug AUC/MIC ratios were 89.3 ± 46.7 and 67.7 ± 35 for the 24-h treatment and 59.6 ± 22 and 33.3 ± 25.5 for the 96-h treatment. These differences were not statistically significant. Pharmacodynamic targets for two non-albicans Candida species were also explored. The mean ED50 (expressed in mg/kg/12 h) and associated 24-h free-drug AUC/MIC ratios were 31.2 and 6.2 for Candida tropicalis (n = 1) and 50.5 and 1.6 for Candida glabrata (n = 2). These PD targets were significantly different from C. albicans targets (P, 0.04). Isavuconazole PD targets for C. albicans are similar to those observed in this model with other triazoles. However, the PD targets for non-albicans Candida species were more than 10-fold lower than those for C. albicans (P, 0.04). This difference is similar to the species-specific PD relationships for the echinocandins. The lower PD targets for these species in this model will be important to consider in the analysis of clinical trial data and during the development of susceptibility breakpoints.

Project description:Oropharyngeal candidiasis (OPC) is the most prevalent oral infection in immunocompromised patients, primarily associated with Candida albicans. Increasing evidence points to a significant role of mucosal bacteria on the transition of C. albicans from commensal to pathogenic. In this work, we hypothesized that changes in the abundance or composition of the mucosal bacterial microbiota induced by dietary sucrose during the development of OPC can modulate C. albicans virulence. C. albicans burdens and mucosal lesions were evaluated in a mouse cortisone immunosuppression model amended with sucrose. We also analyzed the mucosal bacterial composition using 16S rRNA gene sequencing and culture methods. In immunocompetent mice, sucrose significantly increased total bacterial burdens and reduced alpha diversity, by increasing the relative abundance of mitis group streptococci. In immunocompromised mice, C. albicans infection was associated with a significantly reduced bacterial alpha diversity due to an increase in the relative abundance of enterococci. When exposed to dietary sucrose, these mice had reduced C. albicans burdens and reduced bacterial alpha diversity, associated with an increase in the relative abundance of Lactobacillus. SparCC correlation networks showed a significant negative correlation between Lactobacillus and Enterococcus in all Candida-infected mice. Depletion of lactobacilli with antibiotic treatment partially restored C. albicans burdens in mice receiving sucrose. In coculture in vitro experiments, mouse oral Lactobacillus johnsonii isolates inhibited growth of Enterococcus faecalis isolates and C. albicans. These results support the hypothesis that the sucrose-induced attenuation of C. albicans virulence was a result of changes in the mucosal bacterial microbiome characterized by a reduction in enterococci and an increase in lactobacilli. IMPORTANCE By comparing Candida albicans virulence and the mucosal bacterial composition in a mouse oral infection model, we were able to dissect the effects of the host environment (immunosuppression), infection with C. albicans, and local modulating factors (availability of sucrose as a carbon source) on the mucosal bacterial microbiome and its role on fungal virulence. We showed that changes in endogenous microbial communities in response to sucrose can lead to attenuation of fungal disease. We also showed that Lactobacillus johnsonii may curtail Candida virulence both by inhibiting its growth and by inhibiting the growth of potentially synergistic bacteria such as enterococci. Our results support the concept that Candida pathogenesis should be viewed in the contexts of both a susceptible host and a mucosal bacterial microbiota conducive to virulence.

Dataset Information

Avirulence of Candida albicans CaHK1 mutants in a murine model of hematogenously disseminated candidiasis.

Publications

Avirulence of Candida albicans CaHK1 mutants in a murine model of hematogenously disseminated candidiasis.

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