A highly conserved tRNA modification contributes to C. albicans filamentation and virulence
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PROVIDER: PRJNA819979 | ENA |
REPOSITORIES: ENA
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Project description:tRNA modifications play important roles in maintaining translation accuracy in all domains of life. Disruptions in the tRNA modification machinery, especially of the anticodon stem loop, can be lethal for many bacteria and lead to a broad range of phenotypes in baker’s yeast. Very little is known about the function of tRNA modifications in host-pathogen interactions, where rapidly changing environments and stresses require fast adaptations. We found that two closely related fungal pathogens of humans, the highly pathogenic Candida albicans and its much less pathogenic sister species, Candida dubliniensis, differ in the function of a tRNA-modifying enzyme. This enzyme, Hma1, exhibits speciesspecific effects on the ability of the two fungi to grow in the hypha morphology, which is central to their virulence potential. We show that Hma1 has tRNA-threonylcarbamoyladenosine dehydratase activity, and its deletion alters ribosome occupancy, especially at 37°C—the body temperature of the human host. A C. albicans HMA1 deletion mutant also shows defects in adhesion to and invasion into human epithelial cells and shows reduced virulence in a fungal infection model. This links tRNA modifications to host-induced filamentation and virulence of one of the most important fungal pathogens of humans.
2024-04-04 | GSE199421 | GEO
Project description:The ability of the human pathogenic fungus Candida albicans to switch between yeast-like and filamentous forms of growth has long been linked to pathogenesis. Numerous environmental conditions, including growth at high temperatures, nutrient limitation, and exposure to serum, can trigger this morphological switch and are frequently used in in vitro models to identify genes with roles in filamentation. Previous work has suggested that differences exist between the various in vitro models both in the genetic requirements for filamentation and transcriptional responses to distinct filamentation-inducing media. We compared 10 in vitro models for filamentation and found broad genetic and transcriptomic differences between model systems. Methods: Total RNA was extracted from yeast or filamentous cells grown in liquid media or on solid plates. Samples were tested in biological triplicates. RNASeq libraries were generated beginning with 1.8 ng of total RNA following standardized protocols with the TruSeq RNA v2 kit (Illumina, San Diego). Libraries were diluted to a concentration of 6.0 picomoles and sequenced on a HiSeq2500 and 100 bp single reads were generated. Two lanes were used for each sample.
2017-09-28 | GSE99902 | GEO
Project description:The regulatory mechanism for filamentation includes a complex network of transcription factors that play roles in regulating hyphae associated genes. We identify here a new regulator of filamentation from the zinc cluster transcription factor family. We present evidence suggesting that this transcription factor assists the Nrg1/Brg1 switch regulating hyphal development.
2020-12-31 | GSE143825 | GEO
Project description:Clinical isolates of the human fungal pathogen Candida albicans show significant variation in their ability to undergo in vitro filamentation. In this study, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard laboratory strain, has strain dependent functions, especially during infection.
2024-01-20 | GSE253732 | GEO
Project description:The ability of the fungus Candida albicans to filament and form biofilms contributes to its burden as a leading cause of hospital-acquired infections. Biofilm development involves an interconnected transcriptional regulatory network (TRN) consisting of nine transcription factors (TFs) that bind both to their own regulatory regions and to those of the other network TFs. Here, we show that seven of the nine TFs in the C. albicans biofilm network contain prion-like domains (PrLDs) that have been linked to the ability to form phase-separated condensates. Construction of PrLD mutants in four biofilm TFs reveals that these domains are essential for filamentation and biofilm formation in C. albicans. Moreover, biofilm PrLDs promote the formation of phase-separated condensates in the nuclei of live cells, and PrLD mutations that abolish phase separation (such as the removal of aromatic residues) also prevent biofilm formation. Biofilm TF condensates can selectively recruit other TFs through PrLD-PrLD interactions and can co-recruit RNA polymerase II, implicating condensate formation in the assembly of active transcriptional complexes. Finally, we show that PrLD mutations that block the phase separation of biofilm TFs also prevent filamentation in an in vivo model of gastrointestinal colonization. Together, these studies associate transcriptional condensates with the regulation of filamentation and biofilm formation in C. albicans, and highlight how targeting of PrLD-PrLD interactions could prevent pathogenesis by this species.
2023-11-20 | GSE245897 | GEO
Project description:Candidiasis affects a wide variety of immunocompromised individuals, including HIV/AIDS patients and cancer patients on chemotherapy. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, that are genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo. Unexpectedly, both strains showed a dramatic reduction in organ fungal burden and clearance of infection in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling did not reveal any significant changes in the host immune response to UME6 expression in the NACS. Interestingly, however, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly down-regulated. Our findings are significant because they suggest fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicans.
2019-10-01 | GSE134321 | GEO
Project description:To investigate the pre-vacuolar secretory pathway in Candida albicans, we cloned and analyzed the C. albicans homolog of the Saccharomyces cerevisiae vacuolar protein sorting gene VPS1. C. albicans VPS1 encodes a predicted 694-aa dynamin-like GTPase that is 73.3% similar to S. cerevisiae Vps1p. Plasmids bearing C. albicans VPS1 complemented the temperature-sensitive growth, abnormal class F vacuolar morphology, and carboxypeptidase missorting of a S. cerevisiae vps1 null mutant. To study VPS1 function in C. albicans, a conditional mutant strain (tetR-VPS1) was generated by deleting the first allele of VPS1 and placing the second allele under control of a tetracycline-regulatable promoter. With doxycycline, the tetR-VPS1 mutant was hyper-susceptible to sub-inhibitory concentrations of fluconazole, but not amphotericin B, 5-fluorocytosine, or non-specific osmotic stresses. The repressed tetR-VPS1 mutant was defective in filamentation and secreted less extracellular protease activity. Biofilm production and filamentation within the biofilm were markedly reduced. These results suggest that C. albicans VPS1 has a key role in several important virulence-related phenotypes.
| S-EPMC2729247 | biostudies-literature
Project description:The opportunistic pathogenic fungus Candida albicans can cause devastating infections in severely compromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and cause damage, and the expression of a number of pathogenetic mechanisms are also coordinately regulated with this yeast-to-hyphae conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small molecule inhibitors of C. albicans filamentation, and characterized its activity, both in vitro and in vivo, as a promising candidate for the development of alternative anti-virulence strategies for the treatment of C. albicans infections. Here we have performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall treatment with compound 9029936 resulted in 618 up-regulated and 702 down-regulated genes. Not surprisingly some of the top down-regulated genes included well characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an over-representation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among down-regulated genes as result of treatment with this leading compound. Interestingly, the top up-regulated genes pointed to an enhancement of vesicular transport pathways, and in particular SNARE interactions.
2019-08-22 | GSE136116 | GEO
Project description:In this study we were interested in studying the role of SAGA subunits in various cellular processes- morphogenetic changes, growth, invasiveness, biofilm formation and to check the role of these subunits under various cellular and genotoxic conditions. In this work, we investigated conditional and null mutants of components of the SAGA complex modules; Ngg1 of the HAT module, Ubp8 of the Dub module, Tra1 of the recruitment module, Spt7 of the architecture module, and Spt8 of the TBP interaction unit to assess their role in processes such as filamentation, invasiveness, and biofilm formation. Spt7 and Spt8 deletion in Candida albicans resulted in ifilamentatation, invasiveness in YPD media at 30 degrees Celsius and also showed sensitivity to antifungal drugs. Wild type SN148 do not make any filaments in YPD at 30 degrees Celsius and didn't show antifungal sensitivity . The aim was to look for transcription profiling of SAGA mutants against wild type to find genes up and down regulated in the mutant especially those ones critical for filamentation, invasiveness and antifungal drug resistance.
2022-03-09 | GSE193907 | GEO
Project description:Candida albicans causes both mucosal and disseminated infections, and its capacity to grow as both yeast and hyphae is a key virulence factor. Hyphal formation is a type of polarized growth, and members of the SR (serine-arginine) family of RNA-binding proteins influence polarized growth of both Saccharomyces cerevisiae and Aspergillus nidulans. Therefore, we investigated whether SR-like proteins affect filamentous growth and virulence of C. albicans. BLAST searches with S. cerevisiae SR-like protein Npl3 (ScNpl3) identified two C. albicans proteins: CaNpl3, an apparent ScNpl3 ortholog, and Slr1, another SR-like RNA-binding protein with no close S. cerevisiae ortholog. Whereas ScNpl3 was critical for growth, deletion of NPL3 in C. albicans resulted in few phenotypic changes. In contrast, the slr1?/? mutant had a reduced growth rate in vitro, decreased filamentation, and impaired capacity to damage epithelial and endothelial cells in vitro. Mice infected intravenously with the slr1?/? mutant strain had significantly prolonged survival compared to that of mice infected with the wild-type or slr1?/? mutant complemented with SLR1 (slr1?/?+SLR1) strain, without a concomitant decrease in kidney fungal burden. Histopathology, however, revealed differential localization of slr1?/? hyphal and yeast morphologies within the kidney. Mice infected with slr1?/? cells also had an increased brain fungal burden, which correlated with increased invasion of brain, but not umbilical vein, endothelial cells in vitro. The enhanced brain endothelial cell invasion was likely due to the increased surface exposure of the Als3 adhesin on slr1?/? cells. Our results indicate that Slr1 is an SR-like protein that influences C. albicans growth, filamentation, host cell interactions, and virulence.
| S-EPMC3639594 | biostudies-literature