Biology subjects

Jenull, S.

Publications and source records attributed to Jenull, S..

4 recordsLinked to original sources

bioRxiv2024

Carbon Dioxide Controls Fungal Fitness and Skin Tropism of Candida auris

The pronounced skin tropism and pan-antifungal resistance traits of the fungal pathogen Candida auris stand out as a serious health threat. Here, we show that a carbonic sensing pathway (CSP) promotes development of resistance to amphotericin B through a reactive oxygen species (ROS) response, as well as ectopic cell wall and membrane lipid homeostasis. Mechanistically, the transcription factor Rca1 acts in cooperation with Efg1 to control the expression and activity of the carbonic anhydrase Nce103 as a key effector component. The conversion of carbon dioxide to bicarbonate provides a direct link to energy metabolism, facilitating colonization and growth on skin tissues. Native mouse and human skin models unequivocally show that the CSP is essential for maintaining skin tropism as well as fungal fitness. Curiously, upon ablation of Rca1 and Efg1, C. auris debilitates efficient growth on native skin. Collectively, our findings highlight critical roles of the CSP in C. auris skin tropism and antifungal drug resistance. The work suggests therapeutic options for disrupting skin colonization and thus preventing infections. Highlights{checkmark} Proteo-transcriptomics links a carbonic sensing pathway (CSP) to C. auris multidrug resistance {checkmark}The Nce103 carbonic anhydrase controls drug resistance as a key component of the CSP {checkmark}The transcription factors Rca1 and Efg1 control Nce103 and link CSP with C. auris skin tropism {checkmark}CSP acts through ectopic ROS response, cell wall architecture and membrane lipid function {checkmark}CSP is required for C. auris fitness and efficient growth and colonization of skin tissues Result contents{checkmark} Integrated omics reveals multidrug-resistant mechanisms in C. auris {checkmark}CO2-sensing controls amphotericin B resistance (AMBR) traits through Rca1 and Efg1 {checkmark}The carbonic anhydrase Nce103 governs susceptibility to amphotericin B {checkmark}The CSP influences AMBR by maintaining reactive oxygen species homeostasis {checkmark}The CSP controls AMBR via cell membrane and cell wall remodelling {checkmark}The CSP regulates fungal fitness through controlling energy metabolism {checkmark}C. auris requires the CSP for skin colonization

microbiology↗

bioRxiv2024

The Candida auris Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence

Candida auris, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase (MAPK) is essential for efficient skin colonization, intradermal persistence, as well as systemic virulence. RNA-seq analysis of wildtype parental and hog1{Delta} mutant strains revealed marked down-regulation of genes involved in processes such as cell adhesion, cell-wall rearrangement, and pathogenesis in hog1{Delta} mutant compared to the wildtype parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell-wall architecture, as the hog1{Delta} mutant demonstrated a significant increase in cell-surface {beta}-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo. Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections. ImportanceCandida auris is a World Health Organization (WHO) fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention (CDC). C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris. Therefore, understanding C. auris skin colonization mechanisms are critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

microbiology↗

bioRxiv2023

Proline catabolism is key to facilitating Candida albicans pathogenicity

Candida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and for growth. We report that put1-/- and put2-/- strains, carrying defective Proline UTilization genes, display remarkable proline sensitivity with put2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate P5C, which inhibits mitochondrial respiration. The put1-/- and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells colonizing a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not of put2-/- cells. Multiple members of the Candida species complex, including C. auris, are capable of using proline as a sole energy source. Our results indicate that a tailored proline metabolic network tuned to the mammalian host environment is a key feature of opportunistic fungal pathogens.

microbiology↗

bioRxiv2020

ATAC-seq identifies chromatin landscapes linked to the regulation of oxidative stress in the human fungal pathogen Candida albicans

Human fungal pathogens often encounter fungicidal stress conditions upon host invasion, but they can swiftly adapt by transcriptional reprogramming that enables pathogen survival. Fungal immune evasion is tightly connected to chromatin regulation. Hence, fungal chromatin modifiers pose alternative treatment options to combat fungal infections. Here, we present an ATAC-seq protocol adapted for the opportunistic pathogen Candida albicans to gain further insight into the interplay of chromatin accessibility and gene expression mounted during fungal adaptation to oxidative stress. The ATAC-seq workflow facilitates the robust detection of genomic regions with accessible chromatin, but also allows for the precise modeling of nucleosome positions in C. albcians. Importantly, the data reveal genes with altered chromatin accessibility in upstream regulatory regions, which correlate with transcriptional regulation during the oxidative stress response. Interestingly, many genes show increased chromatin accessibility yet no change in gene expression upon stress exposure. Such chromatin signatures could predict yet unknown regulatory factors under highly dynamic transcriptional control. In addition, de novo motif analysis in genomic regions with increased chromatin accessibility upon hydrogen peroxide treatment shows significant enrichment for Cap1 binding sites, a major factor of oxidative stress responses in C. albicans. Taken together, the ATAC-seq workflow enables the identification of chromatin signatures and uncovers the dynamics of regulatory mechanisms mediating environmental adaptation of C. albicans to host immune surveillance. ImportanceThe opportunistic fungal pathogen Candida albicans colonizes and infects various tissues and organs of the human host. This is due to its rapid environmental adaptation facilitated by changes in gene expression coupled to chromatin alterations. Recent advances in chromatin profiling approaches, such as the development of ATAC-seq, shed light on the dynamic interplay of chromatin accessibility and transcriptional control. The here presented expansion of the ATAC-seq method to C. albicans demonstrates the robustness of ATAC-seq to detect dynamic modulations of chromatin accessibility in response to oxidative stress. This work serves as a basis to further exploit this application to characterize regulatory mechanisms that drive fungal environmental adaptation, such as during host invasion, and thus, will open novel antifungal treatment strategies targeting fungal chromatin regulation.

microbiology↗