Biology subjects

Van Genechten, W.

Publications and source records attributed to Van Genechten, W..

4 recordsLinked to original sources

bioRxiv2025

Lactic acid influences iron assimilation by a fungal pathogen via the iron reductive uptake pathway

Candida albicans is a fungal commensal of humans that often causes mucosal infections in otherwise healthy individuals, and also serious infections in immunocompromised patients. The capacity of this fungus to colonise and cause disease relies on its ability to grow within the host, adapting to various nutrient restrictions and physicochemical conditions. The presence of alternative carbon sources, such as the lactate produced by the local microbiota, influences C. albicans antifungal drug resistance and immune evasion. In this study, we used genome-wide transcriptomic analysis to investigate the effect of lactate exposure upon metabolic rewiring. We provide evidence that C. albicans cells respond to growth in the presence of lactate at pH 5 by regulating genes encoding micronutrient transporters, notably iron transporters. More specifically, lactate triggers the downregulation of genes on the reductive iron uptake pathway, inferring a diminished requirement for high-affinity iron uptake. This is supported by the observation that lactate promotes the intracellular accumulation of iron by C. albicans cells. Lactate even enhances the growth of iron-transport defective C. albicans cells under iron-limited conditions. Lactate is known to activate protein kinase A (PKA) signalling. However, lactate-induced iron assimilation is PKA-independent. This work provides new insights into the role of lactate in iron homeostasis - two important factors that promote C. albicans virulence in the mammalian host, where nutritional immunity is a key antimicrobial strategy. ImportanceCandida albicans is a major opportunistic fungal pathogen capable of causing life- threatening infections, particularly in immunocompromised individuals. Its ability to adapt to diverse host environments underlies its success as a commensal and pathogen. This study provides new insights into the metabolic flexibility of C. albicans, with a specific focus on how lactate, a common carbon source in host niches, influences iron acquisition and homeostasis. Our findings reveal that, during growth at pH 5, lactate modulates the expression of micronutrient transporters and enhances iron assimilation in C. albicans. These results suggest a role of lactate in promoting iron uptake, potentially facilitating fungal colonization and persistence within the host. By elucidating the molecular and phenotypic consequences of lactate exposure upon iron metabolism, this study contributes to a deeper understanding of host-pathogen interactions.

cell biology↗

bioRxiv2025

Expansion, functional diversification and gene fusion events in the Ato protein family

Candida albicans, a commensal opportunistic pathogen, exhibits remarkable metabolic flexibility and adaptability to environmental changes. In glucose-limited niches, it utilizes alternative carbon sources such as carboxylic acids, which may influence its pathogenicity. In Saccharomyces cerevisiae, the uptake of monocarboxylates occurs through regulated plasma membrane (PM) transport proteins, such as Ato1 (Ady2), which belongs to the Acetate Uptake Transporter (AceTr) family. In C. albicans, these proteins are notably expanded, consisting of ten Ato-like proteins (ATO1-ATO10), whose functions remain unknown. Here, we investigated the role of Ato proteins in carboxylic acid utilization by C. albicans using in-silico and functional analysis. Our data revealed that several C. albicans Atos retain conserved AceTr motifs but possess distinct structural features, including differences in pore radius and binding sites for acetate and lactate. Expression analysis revealed that Ato1, Ato2, Ato3, and Ato6 exhibit distinct cellular localization and expression levels on the plasma membrane, depending on the presence or absence of monocarboxylates. Remarkably, deletion of ATO1 impaired Ato2 and Ato3 expression and caused ER retention of a distinct form of Ato2, suggesting a central regulatory role for Ato1 in the Ato transport system. Finally, we identified a novel Ato-related protein family in vertebrates. This family has three consecutive 6-helix transport domains and a unique C-terminal fusion with Sua5/YciO/YrdC, an enzyme involved in tRNA modification. Overall, our data suggests that the Ato protein family might play a critical role in the utilization of acetic or lactic acids in C. albicans. It also proposes potential functional redundancy among its members, which may contribute to rapid environmental adaptation and pathogenicity.

microbiology↗

bioRxiv2022

Differential sensing by the C. albicans Gpr1 receptor results in morphogenesis, β-glucan masking and survival in macrophages

The human fungal pathogen, Candida albicans, is very proficient at several classical virulence factors such as morphogenesis, adhesion, biofilm formation and immune evasion through {beta}-glucan masking. The protein kinase A (PKA) pathway is involved in both morphogenesis and {beta}-glucan masking. Several signals converge onto the PKA pathway, but it contains only a single upstream G-protein coupled receptor, Gpr1. We identified specific residues within the N-terminal tail of Gpr1 that are required for methionine-induced morphogenesis through Tpk2. Furthermore, we observe that Gpr1-Gpa2 has an active role in exposing glucans. Even though Gpr1 is required for survival when C. albicans is challenged with macrophages, specifically disrupting morphogenesis did not attenuate this survival. Additionally, constitutive {beta}-glucan masking did not improve C. albicans survival rates in the macrophage assay. Taken together, this indicates that Gpr1 may regulate additional mechanisms, possibly through glutamine 461, which are crucial in a macrophage context. Significance StatementCandida albicans is a human fungal pathogen mostly present as a commensal in the gastrointestinal tract. It can rapidly adapt to its everchanging environment through continuous monitoring of extracellular signals. These extracellular signals include methionine and lactate which induce respectively morphogenesis and {beta}-glucan masking through the G-protein coupled receptor, Gpr1. Through a mutagenic approach we different amino acids of the receptor sense methionine and/or lactate but we show that Gpr1 may have an additional ligand that affect its survival in macrophages.

microbiology↗

bioRxiv2021

Photochromic fluorophores enable imaging of lowly-expressed proteins in the autofluorescent fungus Candida albicans

Fluorescence microscopy is a standard research tool in many fields, though collecting reliable images can be difficult in systems characterized by low expressions levels and/or high background fluorescence. We present the combination of a photochromic fluorescent protein and stochastic optical fluctuation imaging (SOFI) to deliver suppression of the background fluorescence. This strategy makes it possible to resolve lowly- or endogenously-expressed proteins, as we demonstrate for Gcn5, a histone acetyltransferase required for complete virulence, and Erg11, the target of the azole antifungals agents in the fungal pathogen C. albicans. We expect that our method can be readily used for sensitive fluorescence measurements in systems characterized by a high background fluorescence. ImportanceUnderstanding the spatial and temporal organization of proteins-of-interest is key to unravel cellular processes and identify novel possible antifungal targets. Only a few therapeutic targets have been discovered in Candida albicans and resistance mechanisms against these therapeutic agents is rapidly acquired. Fluorescence microscopy is a valuable tool to investigate molecular processes and assess the localization of possible antifungal targets. Unfortunately, fluorescence microscopy of C. albicans suffers from extensive autofluorescence. In this work we present the use of a photochromic fluorescent protein and stochastic optical fluctuation imaging to enable imaging of lowly-expressed proteins in C. albicans through the suppression of autofluorescence. This method can be applied in C. albicans research or adapted for other fungal systems allowing the visualization of intricate processes.

cell biology↗