Dataset Information

Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

ABSTRACT: Candida albicans, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence, while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron limitation using deferasirox (an FDA-approved iron chelator for the treatment of patients with iron overload) during murine OPC and assessed deferasirox-treated C. albicans for its interaction with human oral epithelial (OE) cells, neutrophils, and antimicrobial peptides. Therapeutic deferasirox treatment significantly reduced salivary iron levels, while a nonsignificant reduction in the fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model resulted in a significant reduction in the number of C. albicans CFU per gram of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans cells harvested from the tongues of animals undergoing preventive treatment had the differential expression of 106 genes, including those involved in iron metabolism, adhesion, and the response to host innate immunity. Moreover, deferasirox-treated C. albicans cells had a 2-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress) and reduced adhesion to and invasion of OE cells in vitro Thus, deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence.

SUBMITTER: Puri S

PROVIDER: S-EPMC6437492 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

Puri Sumant S Kumar Rohitashw R Rojas Isolde G IG Salvatori Ornella O Edgerton Mira M

Antimicrobial agents and chemotherapy 20190327 4

Candida albicans, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence, while host nutritional immunity deploys iron-binding proteins to sequest ...[more]

PMID: 30718249

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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.

Project description:Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC.

Dataset Information

Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

Publications

Iron Chelator Deferasirox Reduces <i>Candida albicans</i> Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

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