Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways

ABSTRACT Cryptococcus gattii is a pathogenic yeast of humans and other animals which causes disease predominantly in immunocompetent hosts. Infection begins when aerosolized yeast or spores enter the body, triggering an immune response, including engulfment by macrophages. To understand the early tr...

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Autores principales:	Rhys A. Farrer, Christopher B. Ford, Johanna Rhodes, Toni Delorey, Robin C. May, Matthew C. Fisher, Elaine Cloutman-Green, Francois Balloux, Christina A. Cuomo
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Cryptococcus capsule ergosterol host response host-pathogen interactions laccase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6e68a9721caa4eaca8e2abf7fd098260
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id	oai:doaj.org-article:6e68a9721caa4eaca8e2abf7fd098260
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus capsule ergosterol host response host-pathogen interactions laccase Microbiology QR1-502
spellingShingle	Cryptococcus capsule ergosterol host response host-pathogen interactions laccase Microbiology QR1-502 Rhys A. Farrer Christopher B. Ford Johanna Rhodes Toni Delorey Robin C. May Matthew C. Fisher Elaine Cloutman-Green Francois Balloux Christina A. Cuomo Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
description	ABSTRACT Cryptococcus gattii is a pathogenic yeast of humans and other animals which causes disease predominantly in immunocompetent hosts. Infection begins when aerosolized yeast or spores enter the body, triggering an immune response, including engulfment by macrophages. To understand the early transcriptional signals in both the yeast and its mammalian host, we performed a time-course dual-transcriptome sequencing (RNA-seq) experiment for four lineages of C. gattii (lineages VGI to IV) interacting with mouse macrophages at 1, 3, and 6 h postinfection. Comparisons of in vitro to ex vivo gene expression levels indicated that lineage VGII is transcriptionally divergent from non-VGII lineages, including differential expression of genes involved in capsule synthesis, capsule attachment, and ergosterol production. Several paralogous genes demonstrated subfunctionalization between lineages, including upregulation of capsule biosynthesis-related gene CAP2 and downregulation of CAP1 in VGIII. Isolates also compensate for lineage-specific gene losses by overexpression of genetically similar paralogs, including overexpression of capsule gene CAS3 in VGIV, which have lost the CAS31 gene. Differential expression of one in five C. gattii genes was detected following coincubation with mouse macrophages; all isolates showed high induction of oxidative-reduction functions and downregulation of capsule attachment genes. We also found that VGII switches expression of two laccase paralogs (from LAC1 to LAC2) during coincubation of macrophages. Finally, we found that mouse macrophages respond to all four lineages of C. gattii by upregulating FosB/Jun/Egr1 regulatory proteins at early time points. This report highlights the evolutionary breadth of expression profiles among the lineages of C. gattii and the diversity of transcriptional responses at this host-pathogen interface. IMPORTANCE The transcriptional profiles of related pathogens and their responses to host-induced stresses underpin their pathogenicity. Expression differences between related pathogens during host interaction can indicate when and how these genes contribute to virulence, ultimately informing new and improved treatment strategies for those diseases. In this paper, we compare the transcriptional profiles of five isolates representing four lineages of C. gattii in rich media. Our analyses identified key processes, including those involving cell capsule, ergosterol production, and melanin, that are differentially expressed between lineages, and we found that VGII has the most distinct profile in terms of numbers of differentially expressed genes. All lineages have also undergone subfunctionalization for several paralogs, including capsule biosynthesis and attachment genes. Most genes appeared downregulated during coincubation with macrophages, with the largest decrease observed for capsule attachment genes, which appeared to be coordinated with a stress response, as all lineages also upregulated oxidative stress response genes. Furthermore, VGII upregulated many genes that are linked to ergosterol biosynthesis and switched from expression of the laccase LAC1 to expression of LAC2 ex vivo. Finally, we saw a pronounced increase in the FosB/Jun/Egr1 regulatory proteins at early time points in bone marrow-derived macrophages, marking a role in the host response to C. gattii. This work highlights the dynamic roles of key C. gattii virulence genes in response to macrophages.
format	article
author	Rhys A. Farrer Christopher B. Ford Johanna Rhodes Toni Delorey Robin C. May Matthew C. Fisher Elaine Cloutman-Green Francois Balloux Christina A. Cuomo
author_facet	Rhys A. Farrer Christopher B. Ford Johanna Rhodes Toni Delorey Robin C. May Matthew C. Fisher Elaine Cloutman-Green Francois Balloux Christina A. Cuomo
author_sort	Rhys A. Farrer
title	Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
title_short	Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
title_full	Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
title_fullStr	Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
title_full_unstemmed	Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways
title_sort	transcriptional heterogeneity of <italic toggle="yes">cryptococcus gattii</italic> vgii compared with non-vgii lineages underpins key pathogenicity pathways
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/6e68a9721caa4eaca8e2abf7fd098260
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spelling	oai:doaj.org-article:6e68a9721caa4eaca8e2abf7fd0982602021-11-15T15:22:26ZTranscriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways10.1128/mSphere.00445-182379-5042https://doaj.org/article/6e68a9721caa4eaca8e2abf7fd0982602018-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00445-18https://doaj.org/toc/2379-5042ABSTRACT Cryptococcus gattii is a pathogenic yeast of humans and other animals which causes disease predominantly in immunocompetent hosts. Infection begins when aerosolized yeast or spores enter the body, triggering an immune response, including engulfment by macrophages. To understand the early transcriptional signals in both the yeast and its mammalian host, we performed a time-course dual-transcriptome sequencing (RNA-seq) experiment for four lineages of C. gattii (lineages VGI to IV) interacting with mouse macrophages at 1, 3, and 6 h postinfection. Comparisons of in vitro to ex vivo gene expression levels indicated that lineage VGII is transcriptionally divergent from non-VGII lineages, including differential expression of genes involved in capsule synthesis, capsule attachment, and ergosterol production. Several paralogous genes demonstrated subfunctionalization between lineages, including upregulation of capsule biosynthesis-related gene CAP2 and downregulation of CAP1 in VGIII. Isolates also compensate for lineage-specific gene losses by overexpression of genetically similar paralogs, including overexpression of capsule gene CAS3 in VGIV, which have lost the CAS31 gene. Differential expression of one in five C. gattii genes was detected following coincubation with mouse macrophages; all isolates showed high induction of oxidative-reduction functions and downregulation of capsule attachment genes. We also found that VGII switches expression of two laccase paralogs (from LAC1 to LAC2) during coincubation of macrophages. Finally, we found that mouse macrophages respond to all four lineages of C. gattii by upregulating FosB/Jun/Egr1 regulatory proteins at early time points. This report highlights the evolutionary breadth of expression profiles among the lineages of C. gattii and the diversity of transcriptional responses at this host-pathogen interface. IMPORTANCE The transcriptional profiles of related pathogens and their responses to host-induced stresses underpin their pathogenicity. Expression differences between related pathogens during host interaction can indicate when and how these genes contribute to virulence, ultimately informing new and improved treatment strategies for those diseases. In this paper, we compare the transcriptional profiles of five isolates representing four lineages of C. gattii in rich media. Our analyses identified key processes, including those involving cell capsule, ergosterol production, and melanin, that are differentially expressed between lineages, and we found that VGII has the most distinct profile in terms of numbers of differentially expressed genes. All lineages have also undergone subfunctionalization for several paralogs, including capsule biosynthesis and attachment genes. Most genes appeared downregulated during coincubation with macrophages, with the largest decrease observed for capsule attachment genes, which appeared to be coordinated with a stress response, as all lineages also upregulated oxidative stress response genes. Furthermore, VGII upregulated many genes that are linked to ergosterol biosynthesis and switched from expression of the laccase LAC1 to expression of LAC2 ex vivo. Finally, we saw a pronounced increase in the FosB/Jun/Egr1 regulatory proteins at early time points in bone marrow-derived macrophages, marking a role in the host response to C. gattii. This work highlights the dynamic roles of key C. gattii virulence genes in response to macrophages.Rhys A. FarrerChristopher B. FordJohanna RhodesToni DeloreyRobin C. MayMatthew C. FisherElaine Cloutman-GreenFrancois BallouxChristina A. CuomoAmerican Society for MicrobiologyarticleCryptococcuscapsuleergosterolhost responsehost-pathogen interactionslaccaseMicrobiologyQR1-502ENmSphere, Vol 3, Iss 5 (2018)

Transcriptional Heterogeneity of <italic toggle="yes">Cryptococcus gattii</italic> VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways

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