Processing of
 Candida albicans
 Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence

Richardson, Jonathan P.; Mogavero, Selene; Moyes, David L.; Blagojevic, Mariana; Krüger, Thomas; Verma, Akash; Coleman, Bianca M.; Diaz, Jacinto De La Cruz; Schulz, Daniela; Ponde, Nicole O.; Carrano, Giulia; Kniemeyer, Olaf; Wilson, Duncan; Bader, Oliver; Enoiu, Simona I.; Ho, Jemima; Kichik, Nessim; Gaffen, Sarah L.; Hube, Bernhard; Naglik, Julian R.

doi:10.1128/mbio.02178-17

Cited by 74 publications

(83 citation statements)

References 37 publications

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“…Indeed, as the results in Figure 3 show, C. albicans induces FGF-2 secretion only when it can produce functional candidalysin., However, when spent medium from C. albicans hyphal cultures was added to HUVECs, we did not observe a considerable change in FGF-2 secretion ( Figure S4): this may be due to candidalysin instability in the culture medium. This would be consistent with the recent observation that epithelial cells challenged with C. albicans hyphae, they were damaged, but when the exhausted culture medium was used to infect a fresh epithelial culture, no damage was observed (discussed in [53]). Nevertheless, our results strongly support the assertion that candidalysin is primarily responsible for eliciting the host FGF-2 response.…”

Section: Discussionsupporting

confidence: 91%

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

Vellanki¹,

Huh²,

Saville³

et al. 2019

Preprint

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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 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 expression in vitro, and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 expression 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.

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Section: Discussionsupporting

confidence: 91%

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

Vellanki¹,

Huh²,

Saville³

et al. 2019

Preprint

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“…Modeling and biochemical analyses have revealed that these KR sites are cleavable by the secretory Kex2p protease, resulting in eight peptides of variable length [77,78]. Disruption of these cleavage sites by alanine scanning and use of a ∆/∆kex2 mutant confirmed this suspected secretion mechanism [79]. While the role of seven of these peptides remains enigmatic, peptide three (N-SIIGIIMGILGNIPQVIQIIMSIVKAFKGNK) exhibits lytic activity reminiscent of bacterial cytolysins and the capacity to elicit innate inflammatory pathways (e.g., MAPK) in epithelial and endothelial cells.…”

Section: An Indispensable Role For Candidalysinmentioning

confidence: 89%

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Willems

Ahmed

Liu

et al. 2020

JoF

180

166

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Candida albicans, along with other closely related Candida species, are the primary causative agents of vulvovaginal candidiasis (VVC)-a multifactorial infectious disease of the lower female reproductive tract resulting in pathologic inflammation. Unlike other forms of candidiasis, VVC is a disease of immunocompetent and otherwise healthy women, most predominant during their child-bearing years. While VVC is non-lethal, its high global incidence and profound negative impact on quality-of-life necessitates further understanding of the host and fungal factors that drive disease pathogenesis. In this review, we cover the current state of our understanding of the epidemiology, host response, fungal pathogenicity mechanisms, impact of the microbiome, and novel approaches to treatment of this most prevalent human candidal infection. We also offer insight into the latest advancements in the VVC field and identify important questions that still remain.

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“…While gut bacterial dysbiosis clearly plays a pathogenic role, recent studies suggest that the fungal microbiota is equally important in human physiology and various inflammatory diseases, including IBD (7). The inflammatory response to oral challenges by Candida albicans has been linked to its secretion of the toxic protein candidalysin, causing epithelial damage (8,9). In contrast, anti-inflammatory effects are induced in mouse IBD by oral challenge with other fungi, such as Saccharomyces boulardii, or ␤-glucan, a major component of fungal cell walls (10,11).…”

mentioning

confidence: 99%

Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners

Louis

Mercer

et al. 2019

Infect Immun

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Chitin is a natural N-acetylglucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs; 1- to 10-μm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals of this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice and (ii) whether host chitin-binding Toll-like receptor 2 (TLR2) and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCBs; 40 to 70 μm) but not by chitosan (deacetylated chitin) microparticles, oligosaccharide chitin, or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.

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Processing of Candida albicans Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence

Cited by 74 publications

References 37 publications

<em></em><em>Candida albicans </em>Morphology Dependent Host FGF-2 Response as a Potential Therapeutic Target

<em></em><em>Candida albicans </em>Morphology Dependent Host FGF-2 Response as a Potential Therapeutic Target

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners

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