Cargando…

Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion

The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. a...

Descripción completa

Detalles Bibliográficos
Autores principales: Citiulo, Francesco, Jacobsen, Ilse D., Miramón, Pedro, Schild, Lydia, Brunke, Sascha, Zipfel, Peter, Brock, Matthias, Hube, Bernhard, Wilson, Duncan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386192/
https://www.ncbi.nlm.nih.gov/pubmed/22761575
http://dx.doi.org/10.1371/journal.ppat.1002777
_version_ 1782236943741878272
author Citiulo, Francesco
Jacobsen, Ilse D.
Miramón, Pedro
Schild, Lydia
Brunke, Sascha
Zipfel, Peter
Brock, Matthias
Hube, Bernhard
Wilson, Duncan
author_facet Citiulo, Francesco
Jacobsen, Ilse D.
Miramón, Pedro
Schild, Lydia
Brunke, Sascha
Zipfel, Peter
Brock, Matthias
Hube, Bernhard
Wilson, Duncan
author_sort Citiulo, Francesco
collection PubMed
description The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution.
format Online
Article
Text
id pubmed-3386192
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-33861922012-07-03 Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion Citiulo, Francesco Jacobsen, Ilse D. Miramón, Pedro Schild, Lydia Brunke, Sascha Zipfel, Peter Brock, Matthias Hube, Bernhard Wilson, Duncan PLoS Pathog Research Article The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution. Public Library of Science 2012-06-28 /pmc/articles/PMC3386192/ /pubmed/22761575 http://dx.doi.org/10.1371/journal.ppat.1002777 Text en Citiulo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Citiulo, Francesco
Jacobsen, Ilse D.
Miramón, Pedro
Schild, Lydia
Brunke, Sascha
Zipfel, Peter
Brock, Matthias
Hube, Bernhard
Wilson, Duncan
Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_full Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_fullStr Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_full_unstemmed Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_short Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_sort candida albicans scavenges host zinc via pra1 during endothelial invasion
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386192/
https://www.ncbi.nlm.nih.gov/pubmed/22761575
http://dx.doi.org/10.1371/journal.ppat.1002777
work_keys_str_mv AT citiulofrancesco candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT jacobsenilsed candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT miramonpedro candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT schildlydia candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT brunkesascha candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT zipfelpeter candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT brockmatthias candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT hubebernhard candidaalbicansscavengeshostzincviapra1duringendothelialinvasion
AT wilsonduncan candidaalbicansscavengeshostzincviapra1duringendothelialinvasion