Biology subjects

Tran, V. D. T.

Publications and source records attributed to Tran, V. D. T..

6 recordsLinked to original sources

bioRxiv2025

Genome-guided manipulation of regulators of morphogenesis in a C. albicans strain with low virulence is not sufficient to trigger a high-virulence phenotype

As a member of the microbiome, C. albicans colonizes the oral cavity and other mucosal surfaces of the human body. While commensalism is tightly controlled by the host immune system, the fungal determinants enabling the fungus to colonize the host mucosa without causing tissue damage and inflammation remain less clear. In search of genetic determinants that may underly the commensal lifestyle of the low-virulent C. albicans isolate 101, we identified a small sequence duplication in one of the BRG1 allele resulting in a truncated loss-of-function allele (BRG1TRUNC). Replacing BRG1TRUNC by the full-length allele (BRG1FL) resulted in a modest increase in filamentation, but did not alter the phenotype of the fungus in the oral mucosa of experimentally colonized mice. Spontaneous outgrowth of highly virulent variants of the 101 strain with the BRG1TRUNC alleles replaced by a full-length allele identified the Cyr1-cAMP-PKA signalling pathway as a modulator of fungal virulence. Although the Glu-to-Lys mutation in CYR1 (CYR1E1541K), which converts Cyr1 into a hyperactive adenylate cyclase, greatly increased filamentation, the expression of hyphae-associated genes, and host cell damage when tested in vitro, it was insufficient to increase virulence of C. albicans strain 101 in the oral mucosa in vivo, irrespective of the BRG1 status. Together, this highlights that the low-virulent nature of strain 101 is firmly anchored and cannot be overcome by manipulating BRG1 and CYR1, two genes with known roles in C. albicans virulence. IMPORTANCEDuring homeostasis, the fungus Candida albicans establishes mutualistic interactions with its human host. It can however also adopt a pathogenic state and cause infections with diverse clinical manifestions that pose a significant challenge for diagnosis and therapy. Understanding the fungal determinants that underlie C. albicans colonization under steady state conditions may thus provide new avenues for modulating the fungus-host interaction in candidiasis patients to restore homeostasis. Here, we report gene variants that distinguish high-virulent from low-virulent C. albicans. Gene-exchange mutants provided evidence for the contribution of a BRG1 loss-of-function allele and a CYR1 gain-of-function mutation toward fungal pathogenicity. However, in vivo in an experimental model of C. albicans oral colonization, none of these gene variants individually or in combination were sufficient to change the virulence profile of the fungus. These findings indicate that C. albicans mucosal colonization is regulated by a complex gene network rather than by single genetic determinants.

microbiology↗

bioRxiv2025

Microbiome variations in osteoarthritis reflect aging and metabolic factors, not the disease

The gut microbiome is crucial for human health. Its disruption has been linked to several chronic diseases, including joint disorders. The gut-joint axis has been implicated in the pathogenesis of osteoarthritis (OA), but conflicting findings and study limitations have led to uncertainty regarding the role of microbiota. We conducted a multi-cohort gut microbiota analysis in 1,395 OA patients from four European cohorts (Lifelines, EstMB, FINRISK 2002, TwinsUK), using stringent exclusion criteria and matched controls. When assessing microbial diversity, taxa, functional gene profiles, and gut permeability biomarkers, no significant differences were found between OA and controls. Although this does not exclude a causal contribution of the microbiota in the gut-joint-axis, its dysbiosis does not seem to be linked with OA disease progression. Instead, age and BMI appeared as the main contributing factors to microbiome changes. Microbiome studies in complex diseases often face challenges such as small sample sizes, batch effects, and limited ability to match appropriate controls, particularly in single-cohort designs. By combining data from multiple large cohorts, we were able to mitigate these limitations and provide a more robust assessment of microbiome association with OA. Our findings emphasize the need for rigorous study design in microbiome research and challenge the OA-gut dysbiosis hypothesis.

microbiology↗

bioRxiv2021

Candida albicans commensalism in the oral mucosa is favoured by limited virulence and metabolic adaptation .

As part of the human microbiota, the fungus Candida albicans colonizes the oral cavity and other mucosal surfaces of the human body. Commensalism is tightly controlled by complex interactions of the fungus and the host to preclude fungal elimination but also fungal overgrowth and invasion, which can result in disease. As such, defects in antifungal T cell immunity render individuals susceptible to oral thrush due to interrupted immunosurveillance of the oral mucosa. The factors that promote commensalism and ensure persistence of C. albicans in a fully immunocompetent host remain less clear. Using an experimental model of C. albicans oral colonization in mice we explored fungal determinants of commensalism in the oral cavity. Transcript profiling of the oral isolate 101 in the murine tongue tissue revealed a characteristic metabolic profile tailored to the nutrient poor conditions in the stratum corneum of the epithelium where the fungus resides. Metabolic adaptation of isolate 101 was also reflected in enhanced nutrient acquisition when grown on oral mucosa substrates. Persistent colonization of the oral mucosa by C. albicans also correlated inversely with the capacity of the fungus to induce epithelial cell damage and to elicit an inflammatory response. Here we show that these immune evasive properties of isolate 101 are explained by a strong attenuation of a number of virulence genes, including those linked to filamentation. De-repression of the hyphal program by deletion or conditional repression of NRG1 abolished the commensal behaviour of isolate 101, thereby establishing a central role of this factor in the commensal lifestyle of C. albicans in the oral niche of the host. AUTHOR SUMMARYThe oral microbiota represents an important part of the human microbiota and includes several hundreds to several thousands of bacterial and fungal species. One of the most prominent fungus colonizing the oral cavity is the yeast Candida albicans. While the presence of C. albicans usually remains unnoticed, the fungus can under certain circumstances cause lesions on the lining of the mouth referred to as oral thrush or contribute to other common oral diseases such as caries. Maintaining C. albicans commensalism in the oral mucosa is therefore of utmost importance for oral health and overall wellbeing. While overt fungal growth and disease is limited by immunosurveillance mechanisms during homeostasis, C. albicans strives to survive and evades elimination from the host. Here, we show that while commensalism in the oral cavity is characterized by a restricted fungal virulence and hyphal program, enforcing filamentation in a commensal isolate is sufficient for driving pathogenicity and fungus-induced inflammation in the oral mucosa thwarting persistent colonization. Our results further support a critical role for specialized nutrient acquisition allowing the fungus to thrive in the nutrient poor environment of the squamous epithelium. Together, this work revealed key determinants of C. albicans commensalism in the oral niche.

microbiology↗

bioRxiv2020

MetaNetX/MNXref - unified namespace for metabolites and biochemical reactions in the context of metabolic models

MetaNetX/MNXref is a reconciliation of metabolites and biochemical reactions providing cross-links between major public biochemistry and Genome-Scale Metabolic Network (GSMN) databases. The new release brings several improvements with respect to the quality of the reconciliation, with particular attention dedicated to preserving the intrinsic properties of GSMN models. The MetaNetX website (https://www.metanetx.org/) provides access to the full database and online services. A major improvement is for mapping of user-provided GSMNs to MXNref, which now provides diagnostic messages about model content. In addition to the website and flat files, the resource can now be accessed through a SPARQL endpoint (https://rdf.metanetx.org).

systems biology↗

bioRxiv2017

Gene set enrichment analysis using RNA-seq-based condition-specific metabolic networks

MotivationGenome-scale metabolic networks and transcriptomic data represent complementary sources of knowledge about an organisms metabolism, yet their integration to achieve biological insight remains challenging.\n\nResultsWe investigate here condition-specific series of metabolic sub-networks constructed by successively removing genes from a comprehensive network. The optimal order of gene removal is deduced from transcriptomic data. The sub-networks are evaluated via a fitness function, which estimates their degree of alteration. We then consider how a gene set, i.e. a group of genes contributing to a common biological function, is depleted in different series of sub-networks to detect the difference between experimental conditions. The method, named metaboGSE, is validated on public data for Yarrowia lipolytica and mouse. It is shown to produce GO terms of higher specificity compared to popular gene set enrichment methods like GSEA or topGO.\n\nAvailabilityThe metaboGSE R package is available at https://cran.r-project.org/web/packages/metaboGSE.

systems biology↗

bioRxiv2017

Comparative Genomics Of Two Sequential Candida glabrata Clinical Isolates

Candida glabrata is an important fungal pathogen which develops rapidly antifungal resistance in treated patients. It is known that azole treatments lead to antifungal resistance in this fungal species and that multidrug efflux transporters are involved in this process. Specific mutations in the transcriptional regulator PDR1 result in upregulation of the transporters. In addition, we showed that the PDR1 mutations can contribute to enhance virulence in animal models. We were interested in this study to compare genomes of two specific C. glabrata related isolates, one of which was azole-susceptible (DSY562) while the other was azole-resistant (DSY565). DSY565 contained a PDR1 mutation (L280F) and was isolated after a time lapse of 50 days of azole therapy. We expected that genome comparisons between both isolates could reveal additional mutations reflecting host adaptation or even additional resistance mechanisms. The PacbBio technology used here yielded 14 major contigs (sizes 0.18 Mb-1.6 Mb) and mitochondrial genomes from both DSY562 and DSY565 isolates that were highly similar to each other. Comparisons of the clinical genomes with the published CBS138 genome indicated important genome rearrangements, but not between the clinical strains. Among unique features, several retrotransposons were identified in the genomes of the investigated clinical isolates. DSY562 and DSY565 contained each a large set of adhesin-like genes (101 and 107, respectively), which exceed by far the number of reported adhesins (66) in the CBS138 genome. Comparison between DSY562 and DSY565 yielded 17 non-synonymous SNPs (among which the expected PDR1 mutation) as well as small size indels in coding regions (11) but mainly in adhesin-like genes. The genomes were containing a DNA mismatch repair allele of MSH2 known to be involved in the so-called hypermutator phenotype of this yeast species and the number of accumulated mutations between both clinical isolates is consistent with the presence of a MSH2 defect. In conclusion, this study is the first to compare genomes of C. glabrata sequential clinical isolates using the PacBio technology as an approach. The genomes of these isolates taken in the same patient at two different time points were exhibiting limited variations, even if submitted to the host pressure.

genomics↗