Candida albicans Morphology-Dependent Host FGF-2 Response as a Potential Therapeutic Target.

Eun Huh,Stephen Saville,Sandeep Vellanki,Soo Lee

doi:10.3390/jof5010022

Abstract

Angiogenesis mediated by proteins such as Fibroblast Growth Factor-2 (FGF-2) is a vital component of normal physiological processes and has also been implicated in contributing to the disease state associated with various microbial infections. Previous studies by our group and others have shown that Candida albicans, a common agent of candidiasis, induces FGF-2 secretion in vitro and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 production and the role(s) that FGF-2/angiogenesis plays in C. albicans disease remain unknown. Here we show, for the first time, that C. albicans hyphae (and not yeast cells) increase the FGF-2 response in human endothelial cells. Moreover, Candidalysin, a toxin secreted exclusively by C. albicans in the hyphal state, is required to induce this response. Our in vivo studies show that in the systemic C. albicans infection model, mice treated with FGF-2 exhibit significantly higher mortality rates when compared to untreated mice not given the angiogenic growth factor. Even treatment with fluconazole could not fully rescue infected animals that were administered FGF-2. Our data suggest that the increase of FGF-2 production/angiogenesis induced by Candidalysin contributes to the pathogenicity of C. albicans.

Highlights

Candida albicans is a commensal/opportunistic fungal pathogen most commonly associated with mucosal diseases in humans
We did not observe a substantial change in Human Umbilical Vein Endothelial Cells (HUVECs) challenged with the efg1∆/∆ and tet-NRG1 (−dox) strains
An Enzyme Linked Immuno Sorbent Assay (ELISA) was performed on supernatants from wells with C. albicans only; as expected, no Fibroblast Growth Factor-2 (FGF-2) protein above background could be detected (Figure S2)

Summary

Introduction

Candida albicans is a commensal/opportunistic fungal pathogen most commonly associated with mucosal diseases in humans. Lethal infections by C. albicans are continuously increasing in parallel with the growing proportion of vulnerable individuals such as immunocompromised patients and/or patients with indwelling medical devices [1,2,3]. Many of the antifungal drugs that are currently used in clinical practice target fungal cells by inhibiting their growth or by killing them; they include azoles (targeting ergosterol synthesis), polyenes (physiochemically targeting ergosterol), and echinocandins (targeting cell wall synthesis) [5]. Like many other microbial pathogens, C. albicans can develop resistance against antifungal drugs via (1) mutations in drug target genes, (2) up-regulation of multidrug resistance genes, or (3) the. Many clinical C. albicans isolates are multidrug resistant, and the emergence of drug resistance often leads to poor outcome in the treatment [8]

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Conclusion