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Regulation of Candida albicans virulence traits by protein kinases

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

SEEK ID: https://funginet.hki-jena.de/projects/29

Public web page: http://www.funginet.de/project-c2.html

Organisms: Candida albicans

INF PALs: No PALs for this Project

Project created: 21st Jul 2015

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The zinc cluster transcription factor Czf1 regulates cell wall architecture and integrity in Candida albicans.
C2

Abstract (Expand)

The fungal cell wall is essential for the maintenance of cellular integrity and mediates interactions of the cells with the environment. It is a highly flexible organelle whose composition and organization … is modulated in response to changing growth conditions. In the pathogenic yeast Candida albicans, a network of signaling pathways regulates the structure of the cell wall, and mutants with defects in these pathways are hypersensitive to cell wall stress. By harnessing a library of genetically activated forms of all C. albicans zinc cluster transcription factors, we found that a hyperactive Czf1 rescued the hypersensitivity to cell wall stress of different protein kinase deletion mutants. The hyperactive Czf1 induced the expression of many genes with cell wall-related functions and caused visible changes in the cell wall structure. C. albicans czf1Delta mutants were hypersensitive to the antifungal drug caspofungin, which inhibits cell wall biosynthesis. The changes in cell wall architecture caused by hyperactivity or absence of Czf1 resulted in an increased recognition of C. albicans by human neutrophils. Our results show that Czf1, which is known as a regulator of filamentous growth and white-opaque switching, controls the expression of cell wall genes and modulates the architecture of the cell wall.

Authors: Austin Mottola, Bernardo Ramirez-Zavala, Kerstin Hünniger, Oliver Kurzai, Joachim Morschhäuser

Date Published: 15th Apr 2021

Journal: Mol Microbiol

Metabolic modeling predicts specific gut bacteria as key determinants for Candida albicans colonization levels.
INF, A5, C1, C2, B5

Abstract (Expand)

Candida albicans is a leading cause of life-threatening hospital-acquired infections and can lead to Candidemia with sepsis-like symptoms and high mortality rates. We reconstructed a genome-scale C. … albicans metabolic model to investigate bacterial-fungal metabolic interactions in the gut as determinants of fungal abundance. We optimized the predictive capacity of our model using wild type and mutant C. albicans growth data and used it for in silico metabolic interaction predictions. Our analysis of more than 900 paired fungal-bacterial metabolic models predicted key gut bacterial species modulating C. albicans colonization levels. Among the studied microbes, Alistipes putredinis was predicted to negatively affect C. albicans levels. We confirmed these findings by metagenomic sequencing of stool samples from 24 human subjects and by fungal growth experiments in bacterial spent media. Furthermore, our pairwise simulations guided us to specific metabolites with promoting or inhibitory effect to the fungus when exposed in defined media under carbon and nitrogen limitation. Our study demonstrates that in silico metabolic prediction can lead to the identification of gut microbiome features that can significantly affect potentially harmful levels of C. albicans.

Authors: Mohammad Mirhakkak, Sascha Schäuble, Tilman Klassert, S. Brunke, Philipp Brandt, D. Loos, R. V. Uribe, F. Senne de Oliveira Lino, Y. Ni, Slavena Vylkova, Hortense Slevogt, Bernhard Hube, Esther Weiß, M. O. A. Sommer, Gianni Panagiotou

Date Published: 15th Dec 2020

Journal: ISME J

Active neutrophil responses counteract Candida albicans burn wound infection of ex vivo human skin explants.
FungiNet C - Candida projects, C2

Abstract (Expand)

Burn wounds are highly susceptible sites for colonization and infection by bacteria and fungi. Large wound surface, impaired local immunity, and broad-spectrum antibiotic therapy support growth of … opportunistic fungi such as Candida albicans, which may lead to invasive candidiasis. Currently, it remains unknown whether depressed host defenses or fungal virulence drive the progression of burn wound candidiasis. Here we established an ex vivo burn wound model, where wounds were inflicted by applying preheated soldering iron to human skin explants, resulting in highly reproducible deep second-degree burn wounds. Eschar removal by debridement allowed for deeper C. albicans penetration into the burned tissue associated with prominent filamentation. Active migration of resident tissue neutrophils towards the damaged tissue and release of pro-inflammatory cytokine IL-1beta accompanied the burn. The neutrophil recruitment was further increased upon supplementation of the model with fresh immune cells. Wound area and depth decreased over time, indicating healing of the damaged tissue. Importantly, prominent neutrophil presence at the infected site correlated to the limited penetration of C. albicans into the burned tissue. Altogether, we established a reproducible burn wound model of candidiasis using ex vivo human skin explants, where immune responses actively control the progression of infection and promote tissue healing.

Authors: C. von Muller, F. Bulman, L. Wagner, D. Rosenberger, A. Marolda, Oliver Kurzai, P. Eissmann, Ilse Jacobsen, B. Perner, P. Hemmerich, Slavena Vylkova

Date Published: 11th Dec 2020

Journal: Sci Rep

Catch the wave: Metabolomic analyses in human pathogenic fungi.
C2

Abstract

Not specified

Authors: Philipp Brandt, E. Garbe, Slavena Vylkova

Date Published: 21st Aug 2020

Journal: PLoS Pathog

Generation of Viable Candida albicans Mutants Lacking the "Essential" Protein Kinase Snf1 by Inducible Gene Deletion.
C2

Abstract (Expand)

The protein kinase Snf1, a member of the highly conserved AMP-activated protein kinase family, is a central regulator of metabolic adaptation. In the pathogenic yeast Candida albicans, Snf1 is considered … to be essential, as previous attempts by different research groups to generate homozygous snf1Delta mutants were unsuccessful. We aimed to elucidate why Snf1 is required for viability in C. albicans by generating snf1Delta null mutants through forced, inducible gene deletion and observing the terminal phenotype before cell death. Unexpectedly, we found that snf1Delta mutants were viable and could grow, albeit very slowly, on rich media containing the preferred carbon source glucose. Growth was improved when the cells were incubated at 37 degrees C instead of 30 degrees C, and this phenotype enabled us to isolate homozygous snf1Delta mutants also by conventional, sequential deletion of both SNF1 alleles in a wild-type C. albicans strain. All snf1Delta mutants could grow slowly on glucose but were unable to utilize alternative carbon sources. Our results show that, under optimal conditions, C. albicans can live and grow without Snf1. Furthermore, they demonstrate that inducible gene deletion is a powerful method for assessing gene essentiality in C. albicans IMPORTANCE Essential genes are those that are indispensable for the viability and growth of an organism. Previous studies indicated that the protein kinase Snf1, a central regulator of metabolic adaptation, is essential in the pathogenic yeast Candida albicans, because no homozygous snf1 deletion mutants of C. albicans wild-type strains could be obtained by standard approaches. In order to investigate the lethal consequences of SNF1 deletion, we generated conditional mutants in which SNF1 could be deleted by forced, inducible excision from the genome. Unexpectedly, we found that snf1 null mutants were viable and could grow slowly under optimal conditions. The growth phenotypes of the snf1Delta mutants explain why such mutants were not recovered in previous attempts. Our study demonstrates that inducible gene deletion is a powerful method for assessing gene essentiality in C. albicans.

Authors: Austin Mottola, S. Schwanfelder, Joachim Morschhäuser

Date Published: 19th Aug 2020

Journal: mSphere

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