Article

The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2009; 106(31):12980-5. DOI: 10.1073/pnas.0902963106
Source: PubMed

ABSTRACT

In 1999, the population of Vancouver Island, Canada, began to experience an outbreak of a fatal fungal disease caused by a highly virulent lineage of Cryptococcus gattii. This organism has recently spread to the Canadian mainland and Pacific Northwest, but the molecular cause of the outbreak remains unknown. Here we show that the Vancouver Island outbreak (VIO) isolates have dramatically increased their ability to replicate within macrophages of the mammalian immune system in comparison with other C. gattii strains. We further demonstrate that such enhanced intracellular parasitism is directly linked to virulence in a murine model of cryptococcosis, suggesting that this phenotype may be the cause of the outbreak. Finally, microarray studies on 24 C. gattii strains reveals that the hypervirulence of the VIO isolates is characterized by the up-regulation of a large group of genes, many of which are encoded by mitochondrial genome or associated with mitochondrial activities. This expression profile correlates with an unusual mitochondrial morphology exhibited by the VIO strains after phagocytosis. Our data thus demonstrate that the intracellular parasitism of macrophages is a key driver of a human disease outbreak, a finding that has significant implications for a wide range of other human pathogens.

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    • "In the case of C. gattii outbreak isolates, rapid intracellular proliferation is associated with changes in mitochondrial morphology (Ma et al. 2009; Voelz et al. 2014). It was initially proposed that this change in mitochondrial morphology could protect the pathogen against the intracellular environment of the phagocytic cells (Ma et al. 2009 ; Ma and May 2010). However, more recent analyses of this group have indicated a more complex and intriguing model. "
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    ABSTRACT: Cryptococcosis is an invasive fungal infection of humans and other animals, typically caused by the species Cryptococcus neoformans in patients with impaired immunity. However, there is growing recognition of the importance of the related species C. gattii in causing infections in apparently immunocompetent individuals. In particular, an ongoing outbreak of cryptococcal disease in the Pacific Northwest region, which started in 1999, has driven an intense research effort into this previously neglected pathogen. Here, we discuss some of the recent discoveries in this organism from the Pacific Northwest region and highlight areas for future investigation.
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    • "The mitochondrial-related proteins GOA1 and SOD2 in Candida albicans are required for virulence (Bambach et al. 2009; Becker et al. 2010; Noble et al. 2010). A role for mitochondria in hypervirulence was reported for Cryptococcus gattii and it was proposed that this positive role of mitochondria function in virulence is due to the change in mitochondrial morphology toward more tubular-structured organelles (Byrnes et al. 2010; Ma et al. 2009). Shingu-Vazquez and Traven (2011) reported in their 2011 review that the reduced virulence associated with dysfunctional mitochondria is probably due to reduced fitness, metabolic changes, and sensitivity to oxidative stress caused by defective respiration. "
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    ABSTRACT: The mitochondrial fission protein Fis1 regulates yeast mitochondrial fission and is required for ethanol-induced mitochondrial fragmentation and apoptosis. To examine the function of Fis1 in a plant pathogenic fungus, we cloned the MoFIS1 gene, a homolog of Saccharomyces cerevisiae FIS1, from Magnaporthe oryzae and characterized its function by targeted gene deletion and mutant phenotypic analysis. MoFIS1 deletion mutants were unaltered in conidial germination, appressorium formation, and mating tests, but were severely defective in colony growth, conidiation, virulence on rice and barley, growth under nitrogen and glucose deficiency, and growth under osmotic stress. Blast lesions on rice leaves caused by the ΔMofis1 strain were significantly reduced, were non-proliferating, and were less coalesced as compared to the highly coalesced and proliferating lesions resulting from infection with the wild-type strain. The defects in growth, conidiation, and virulence of the mutant were restored in a complementation strain of ΔMofis1. A MoFis1-GFP fusion protein co-localized with Mitotracker red in mitochondria. These results show that MoFIS1 encodes a mitochondrial protein that regulates fungal growth, conidiation, and virulence in M. oryzae. Copyright © 2015 Elsevier GmbH. All rights reserved.
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    • "Contrary to previous assumptions [3], [6], [18], [19], the virulence trait is not restricted to Vancouver Island outbreak strains that belong to the major genotype AFLP6A/VGIIA, virulent and non-virulent phenotypes co-occur within recently emerged C. gattii AFLP6/VGII lineages (Fig. 1). Cryptococcus gattii strains from the Pacific Northwest outbreak had a similar virulence potential in mice and macrophage pathogenicity assays as strains from British Columbia (this study; [3]). "
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    ABSTRACT: Over the past two decades, several fungal outbreaks have occurred, including the high-profile 'Vancouver Island' and 'Pacific Northwest' outbreaks, caused by Cryptococcus gattii, which has affected hundreds of otherwise healthy humans and animals. Over the same time period, C. gattii was the cause of several additional case clusters at localities outside of the tropical and subtropical climate zones where the species normally occurs. In every case, the causative agent belongs to a previously rare genotype of C. gattii called AFLP6/VGII, but the origin of the outbreak clades remains enigmatic. Here we used phylogenetic and recombination analyses, based on AFLP and multiple MLST datasets, and coalescence gene genealogy to demonstrate that these outbreaks have arisen from a highly-recombining C. gattii population in the native rainforest of Northern Brazil. Thus the modern virulent C. gattii AFLP6/VGII outbreak lineages derived from mating events in South America and then dispersed to temperate regions where they cause serious infections in humans and animals.
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