Biphasic zinc compartmentalisation in a human fungal pathogen
| Autor: | Crawford, Aaron C., Lehtovirta-Morley, Laura E., Alamir, Omran, Niemiec, Maria J., Alawfi, Bader, Alsarraf, Mohammad, Skrahina, Volha, Costa, Anna C. B. P., Anderson, Andrew, Yellagunda, Sujan, Ballou, Elizabeth R., Hube, Bernhard, Urban, Constantin F., Wilson, Duncan |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
Yeast and Fungal Models Pathology and Laboratory Medicine Biochemistry Mice Candida albicans Medicine and Health Sciences Biology (General) Cation Transport Proteins Candida Fungal Pathogens Staining Mice Knockout Virulence Eukaryota Cell Staining Hydrogen-Ion Concentration Adaptation Physiological Chemistry Zinc Experimental Organism Systems Medical Microbiology Physical Sciences Host-Pathogen Interactions Saccharomyces Cerevisiae Female Pathogens Anatomy Research Article Chemical Elements QH301-705.5 Genes Fungal Mycology Research and Analysis Methods Microbiology Fungal Proteins Saccharomyces Model Organisms Animals Calgranulin B Humans Candidiasis Invasive Microbial Pathogens Manganese Organisms Fungi Biology and Life Sciences Kidneys Biological Transport Renal System RC581-607 Yeast Cell Compartmentation Mice Inbred C57BL Mikrobiologi Metabolism Specimen Preparation and Treatment Immunologic diseases. Allergy Carrier Proteins Zinc Transporters Leukocyte L1 Antigen Complex Gene Deletion Antimicrobial Cationic Peptides |
| Zdroj: | PLoS Pathogens, Vol 14, Iss 5, p e1007013 (2018) PLoS Pathogens |
| Popis: | Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans. Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C. albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2-null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus, suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C. albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C. albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C. albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C. albicans. Here we show that, unlike in Saccharomyces cerevisiae, C. albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo. In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation. Author summary All living organisms must secure certain trace metals such as iron and zinc in their diets. For the microbes that infect us, the source of these micronutrients is the tissues of their host. However, mammals have developed sophisticated mechanisms to manipulate microbial access to trace metals–a process called nutritional immunity. Therefore, successful pathogenic microorganisms must have evolved mechanisms to counteract nutritional immunity and acquire micronutrients in order to grow within their hosts and cause disease. This struggle for micronutrients represents a key host-pathogen battleground. In this study we demonstrate how the major human fungal pathogen, Candida albicans, acquires and stores zinc from its environment. We find that the mechanistic basis of zinc uptake is highly dependent on the acidity of the surrounding environment. Interestingly, this pH-dependence appears conserved in the fungal kingdom and we propose a potential framework for the evolution of zinc uptake in extant fungal species. Moreover, following cellular assimilation, C. albicans shuttles this potentially toxic transition metal into subcellular compartments called zincosomes. We also show that both zinc uptake and compartmentalisation are critical for C. albicans growth, both under laboratory conditions and in experimental models of invasive candidiasis. |
| Databáze: | OpenAIRE |
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