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


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.

Download full-text


Available from: Ferry Hagen,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Microbiological Research 07/2015; 178. DOI:10.1016/j.micres.2015.06.002 · 2.56 Impact Factor
  • Source
    • "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]). "
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 08/2013; 8(8):e71148. DOI:10.1371/journal.pone.0071148 · 3.23 Impact Factor
  • Source
    • "It can be hypothesized that a specific defect in the innate immune system of affected hosts predisposes them to infection with C. gattii. Furthermore, other factors such as intracellular survival, outgrowth or dissemination may also be important for virulence of C. gattii, independent of the initial pro-inflammatory cytokine response [19]. In our experiments we used PBMCs of healthy individuals who are expected to have an adequate immune response to C. gattii. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding more about the host's immune response to different Cryptococcus spp. will provide additional insight into the pathogenesis of cryptocococcis. We hypothesized that the ability of C. gattii to cause disease in immunocompetent humans depends on a distinct innate cytokine response of the host to this emerging pathogen. In the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with 40 different well-defined heat-killed isolates of C. gattii, C. neoformans and several hybrid strains. In addition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii. Isolates of C. gattii induced higher concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6 and the Th17/22 cytokine IL-17 and IL-22 compared to C. neoformans var neoformans and C. neoformans var grubii. In addition, clinical C. gattii isolates induced higher amounts of cytokines than environmental isolates. This difference was not observed in C. neoformans var. grubii isolates. Furthermore, we demonstrated a likely contribution of TLR4 and TLR9, but no role for TLR2, in the host's cytokine response to C. gattii. In conclusion, clinical heat-killed C. gattii isolates induced a more pronounced inflammatory response compared to other Cryptococcus species and non-clinical C. gattii. This is dependent on TLR4 and TLR9 as cellular receptors.
    PLoS ONE 01/2013; 8(1):e55579. DOI:10.1371/journal.pone.0055579 · 3.23 Impact Factor
Show more