Abstract
Candida albicans, the most prevalent fungal pathogen, undergoes yeast-to-hyphal switch which has long been identified as a key fungal virulence factor. We showed here that the lichen-derived small molecule retigeric acid B (RAB) acted as an inhibitor that significantly inhibited the filamentation of C. albicans, leading to the prolonged survival of nematodes infected by C. albicans. Quantitative real-time PCR analysis and intracellular cAMP measurement revealed RAB regulated the Ras1-cAMP-Efg1 pathway by reducing cAMP level to inhibit the hyphae formation. Confocal microscopic observation showed RAB induced the expression of Dpp3, synthesizing more farnesol, which was confirmed by gas chromatography-mass spectroscopy detection. An adenylyl cyclase activity assay demonstrated RAB could repress the activity of Cdc35 through stimulating farnesol synthesis, thus causing a decrease in cAMP synthesis, leading to retarded yeast-to-hyphal transition. Moreover, reduced levels of intracellular cAMP resulted in the inhibition of downstream adhesins. Together, these findings indicate that RAB stimulates farnesol production that directly inhibits the Cdc35 activity, reducing the synthesis of cAMP and thereby causing the disruption of the morphologic transition and attenuating the virulence of C. albicans. Our work illustrates the underlying mechanism of RAB-dependent inhibition of the yeast-to-hyphal switch and provides a potential application in treating the infection of C. albicans.
Highlights
Candida albicans, an opportunistic human pathogen, causes systemic candidiasis mainly in immunocompromised individuals, with an estimated 40% mortality rate [1]
The Antifungal Efficacy of retigeric acid B (RAB) In vitro and In vivo We first tested the antifungal activity of RAB against C. albicans strains SC5314, YEM30, CASA1, CA2 and CA10 according to the CLSI standard [16]
We found that RAB displayed antifungal activity with 8 or 16 mg/ml of MIC80 against these strains of C. albicans in vitro
Summary
An opportunistic human pathogen, causes systemic candidiasis mainly in immunocompromised individuals, with an estimated 40% mortality rate [1]. The success of C. albicans as the leading fungal pathogen is a result of its virulence factors such as adhesins, phenotypic switch, secreted aspartyl proteases or phospholipases, among which the switch from yeast-to-hyphal was more concerned [2]. The yeast-to-hyphal transition, and upregulation of hyphal-specific genes during the course of infection increase the virulence potential [3]. Filaments have the ability to promote tissue penetration and escape from immune cells, which results in systemic infection accompanied with yeast-form dissemination [4]. A quorum sensing molecule, secreted by C. albicans could regulate the yeast-to-hyphal transition and biofilm formation [6,7]. Agents which could induce the Dpp expression, stimulating more farnesol synthesis, have potential antifungal effect
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
