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Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection

Candida albicans is one of the most common human fungal pathogens. C. albicans pathogenesis is tightly linked to its ability to under a morphogenetic transition from typically budding yeast to filamentous forms of hyphae and pseudohyphae. Filamentous morphogenesis is the most intensively studied C....

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Autores principales: Wakade, Rohan S, Ristow, Laura C, Wellington, Melanie, Krysan, Damian J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995110/
https://www.ncbi.nlm.nih.gov/pubmed/36847358
http://dx.doi.org/10.7554/eLife.85114
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author Wakade, Rohan S
Ristow, Laura C
Wellington, Melanie
Krysan, Damian J
author_facet Wakade, Rohan S
Ristow, Laura C
Wellington, Melanie
Krysan, Damian J
author_sort Wakade, Rohan S
collection PubMed
description Candida albicans is one of the most common human fungal pathogens. C. albicans pathogenesis is tightly linked to its ability to under a morphogenetic transition from typically budding yeast to filamentous forms of hyphae and pseudohyphae. Filamentous morphogenesis is the most intensively studied C. albicans virulence traits; however, nearly all of these studies have been based on in vitro induction of filamentation. Using an intravital imaging assay of filamentation during mammalian (mouse) infection, we have screened a library of transcription factor mutants to identify those that modulate both the initiation and maintenance of filamentation in vivo. We coupled this initial screen with genetic interaction analysis and in vivo transcription profiling to characterize the transcription factor network governing filamentation in infected mammalian tissue. Three core positive (Efg1, Brg1, and Rob1) and two core negative regulators (Nrg1 and Tup1) of filament initiation were identified. No previous systematic analysis of genes affecting the elongation step has been reported and we found that large set of transcription factors affect filament elongation in vivo including four (Hms1, Lys14, War1, Dal81) with no effect on in vitro elongation. We also show that the gene targets of initiation and elongation regulators are distinct. Genetic interaction analysis of the core positive and negative regulators revealed that the master regulator Efg1 primarily functions to mediate relief of Nrg1 repression and is dispensable for expression of hypha-associated genes in vitro and in vivo. Thus, our analysis not only provide the first characterization of the transcriptional network governing C. albicans filamentation in vivo but also revealed a fundamentally new mode of function for Efg1, one of the most widely studied C. albicans transcription factors.
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spelling pubmed-99951102023-03-09 Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection Wakade, Rohan S Ristow, Laura C Wellington, Melanie Krysan, Damian J eLife Microbiology and Infectious Disease Candida albicans is one of the most common human fungal pathogens. C. albicans pathogenesis is tightly linked to its ability to under a morphogenetic transition from typically budding yeast to filamentous forms of hyphae and pseudohyphae. Filamentous morphogenesis is the most intensively studied C. albicans virulence traits; however, nearly all of these studies have been based on in vitro induction of filamentation. Using an intravital imaging assay of filamentation during mammalian (mouse) infection, we have screened a library of transcription factor mutants to identify those that modulate both the initiation and maintenance of filamentation in vivo. We coupled this initial screen with genetic interaction analysis and in vivo transcription profiling to characterize the transcription factor network governing filamentation in infected mammalian tissue. Three core positive (Efg1, Brg1, and Rob1) and two core negative regulators (Nrg1 and Tup1) of filament initiation were identified. No previous systematic analysis of genes affecting the elongation step has been reported and we found that large set of transcription factors affect filament elongation in vivo including four (Hms1, Lys14, War1, Dal81) with no effect on in vitro elongation. We also show that the gene targets of initiation and elongation regulators are distinct. Genetic interaction analysis of the core positive and negative regulators revealed that the master regulator Efg1 primarily functions to mediate relief of Nrg1 repression and is dispensable for expression of hypha-associated genes in vitro and in vivo. Thus, our analysis not only provide the first characterization of the transcriptional network governing C. albicans filamentation in vivo but also revealed a fundamentally new mode of function for Efg1, one of the most widely studied C. albicans transcription factors. eLife Sciences Publications, Ltd 2023-02-27 /pmc/articles/PMC9995110/ /pubmed/36847358 http://dx.doi.org/10.7554/eLife.85114 Text en © 2023, Wakade et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Wakade, Rohan S
Ristow, Laura C
Wellington, Melanie
Krysan, Damian J
Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title_full Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title_fullStr Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title_full_unstemmed Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title_short Intravital imaging-based genetic screen reveals the transcriptional network governing Candida albicans filamentation during mammalian infection
title_sort intravital imaging-based genetic screen reveals the transcriptional network governing candida albicans filamentation during mammalian infection
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995110/
https://www.ncbi.nlm.nih.gov/pubmed/36847358
http://dx.doi.org/10.7554/eLife.85114
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