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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    ABSTRACT: Candida albicans is an opportunistic, fungal pathogen of humans that frequently causes superficial infections of oral and vaginal mucosal surfaces of debilitated and susceptible individuals. The organism is however, commonly encountered as a commensal in healthy individuals where it is a component of the normal microflora. The key determinant in the type of relationship that Candida has with its host is how it interacts with the epithelial surface it colonises. A delicate balance clearly exists between the potentially damaging effects of Candida virulence factors and the nature of the immune response elicited by the host. Frequently, it is changes in host factors that lead to Candida seemingly changing from a commensal to pathogenic existence. However, given the often reported heterogeneity in morphological and biochemical factors that exist between Candida species and indeed strains of C. albicans, it may also be the fact that colonising strains differ in the way they exploit resources to allow persistence at mucosal surfaces and as a consequence this too may affect the way Candida interacts with epithelial cells. The aim of this review is to provide an overview of some of the possible interactions that may occur between C. albicans and host epithelial surfaces that may in turn dictate whether Candida removal, its commensal persistence or infection follows.
    Journal of Oral Microbiology 10/2013; 5. DOI:10.3402/jom.v5i0.22434
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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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    ABSTRACT: Riccardin D, a macrocyclic bisbibenzyl isolated from Chinese liverwort Dumortiera hirsute, has been proved to have inhibitory effect on biofilms formation of Candida albicans in in vitro study. Our present study aims to investigate the in vivo effect and mechanisms of riccardin D against C. albicans biofilms when used alone or in combination with clinical using antifungal agent fluconazole. XTT reduction assay revealed riccardin D had both prophylactic and therapeutic effect against C. albicans biofilms formation in a dose-dependent manner when using a central venous catheter related infective animal model. Scanning electron microscope and laser confocal scanning microscope showed that the morphology of biofilms was altered remarkably after riccardin D treatment, especially hypha growth inhibition. To uncover the underlying molecular mechanisms, quantitative real-time RT-PCR was performed to observe the variation of related genes. The downregulation of hypha-specific genes such as ALS1, ALS3, ECE1, EFG1, HWP1 and CDC35 following riccardin D treatment suggested riccardin D inhibited the Ras-cAMP-Efg pathway to retard the hypha formation, then leading to the defect of biofilms maturation. Moreover, riccardin D displayed an increased antifungal activity when administered in combination with fluconazole. Our study provides a potential clinical application to eliminate the biofilms of relevant pathogens.
    PLoS ONE 04/2012; 7(4):e35543. DOI:10.1371/journal.pone.0035543 · 3.23 Impact Factor
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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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    ABSTRACT: Most of the fungal species that infect humans can grow in more than one morphological form but only a subset of pathogens produce filamentous hyphae during the infection process. This subset is phylogenetically unrelated and includes the commonly carried yeasts, Candida albicans, C. dubliniensis, and Malassezia spp., and the acquired pathogens, Aspergillus fumigatus and dermatophytes such as Trichophyton rubrum and T. mentagrophytes. The primary function of hypha formation in these opportunistic pathogens is to invade the substrate they are adhered to, whether biotic or abiotic, but other functions include the directional translocation between host environments, consolidation of the colony, nutrient acquisition and the formation of 3-dimensional matrices. To support these functions, polarised hyphal growth is co-regulated with other factors that are essential for normal hypha function in vivo.
    International Journal of Microbiology 01/2012; 2012(1687-918X):517529. DOI:10.1155/2012/517529
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