Role of Bcr1-Activated Genes Hwp1 and Hyr1 in Candida Albicans Oral Mucosal Biofilms and Neutrophil Evasion

Department of Microbiology, University of Texas, Houston, Texas, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2011; 6(1):e16218. DOI: 10.1371/journal.pone.0016218
Source: PubMed


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.

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Available from: ZHIHONG XIE, Apr 29, 2014
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    • "An important regulator of C. albicans biofilm formation is the transcription factor Bcr1, which is a positive regulator of several candidal adhesin genes including HYR1, HWP1, CHT2, ECE1, RBT5, ALS1, and ALS3 (43, 44). The importance of Bcr1 in C. albicans biofilm formation within in a mouse model of oral infection has recently been demonstrated (45). "
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    • "In C. albicans, the agglutinin-like sequence (ALS) genes have been revealed to have close relationship with biofilms formation [35], [36]. It was proved that overexpression of ALS3 leads to an increase in biofilms mass [37], while overexpression of HWP1, the necessary factor for normal biofilms formation in vitro and in vivo could effectively restores the ability of a bcr1D null strain to form biofilms on murine mucosal surfaces [38]–[40]. In this study, we found all the genes were downregulated after RCD treatment compared with the control, indicating RCD affects C. albicans biofilms formation by inhibiting Ras-cAMP-Efg signalling pathway. "
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    • "Other transcription factors that lie downstream of the Efg1/Cph1 master regulators have been identified as regulators of subsets of HSGs under defined in vivo conditions. These include Ume6, a master regulator of hypha-specific genes, Czf1 (embedded growth), Bcr1 (biofilm maturation), Eed1 (escape after endocytosis), and Hgc1, which suppresses cell separation and is expressed at the hyphal tip only [39, 67–72]. Analyses of temporal and spatial gene expression during infection, coupled with studies of physical changes induced by the environment in other fungi, suggest that a combination of site-specific and hypha-specific gene expression is likely to produce hyphae with subtly different properties [73, 74]. "
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