Abstract
Candida albicans triggers recurrent infections of the oropharyngeal mucosa that result from biofilm growth. Prior studies have indicated that the transcription factor Bcr1 regulates biofilm formation in a catheter model, both in vitro and in vivo. We thus hypothesized that Bcr1 plays similar roles in the formation of oral mucosal biofilms and tested this hypothesis in a mouse model of oral infection. We found that a bcr1/bcr1 mutant did not form significant biofilm on the tongues of immunocompromised mice, in contrast to reference and reconstituted strains that formed pseudomembranes covering most of the tongue dorsal surface. Overexpression of HWP1, which specifies an epithelial adhesin that is under the transcriptional control of Bcr1, partly but significantly rescued the bcr1/bcr1 biofilm phenotype in vivo. Since HWP1 overexpression only partly reversed the biofilm phenotype, we investigated whether additional mechanisms, besides adhesin down-regulation, were responsible for the reduced virulence of this mutant. We discovered that the bcr1/bcr1 mutant was more susceptible to damage by human leukocytes when grown on plastic or on the surface of a human oral mucosa tissue analogue. Overexpression of HYR1, but not HWP1, significantly rescued this phenotype. Furthermore a hyr1/hyr1 mutant had significantly attenuated virulence in the mouse oral biofilm model of infection. These discoveries show that Bcr1 is critical for mucosal biofilm infection via regulation of epithelial cell adhesin and neutrophil function.
Highlights
Oral pseudomembranous candidiasis is the most prevalent form of Candida infection in patients with weakened or immature immune systems, such as HIV+ children, neonates and patients with malignancies [1,2,3]
Consistent with results in the mouse vaginal mucosa model [16], we found that the bcr1/bcr1 strain was deficient in forming a clinically visible mucosal biofilm on the tongues of immunocompromised mice in vivo (Fig. 1)
At the histologic level this mutant formed a thin, interrupted biofilm on the dorsal surface of the tongue (Fig. 1, arrows). These results are in agreement with the recently reported attenuated biofilm phenotype of a bcr1/bcr1 mutant in the rat denture biofilm model [17]
Summary
Oral pseudomembranous candidiasis (thrush) is the most prevalent form of Candida infection in patients with weakened or immature immune systems, such as HIV+ children, neonates and patients with malignancies [1,2,3]. Manipulation of Bcr1 downstream target genes through mutation and overexpression showed that the surface adhesins Als3 and Hwp1 significantly contribute to biofilm formation in the catheter model. Using both in vivo and in vitro models we tested the ability of this mutant to form biofilms on the oral mucosa and dissected the specific contribution of Bcr1-regulated genes in this phenotype.
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