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Cited by 218Fungal Infections and StudiesGenetic diversity and population structurePlant Pathogens and Fungal Diseases

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Ancient Dispersal of the Human Fungal Pathogen Cryptococcus gattii from the Amazon Rainforest

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Hagen, Ferry, Ceresini, Paulo C., Polacheck, Itzhack, Ma, Hansong, Nieuwerburgh, Filip van, Gabaldón, Toni, Kagan, Sarah, Pursall, E. Rhiannon, Hoogveld, Hans L., van Iersel, Leo J. J., Klau, Gunnar W., Kelk, Steven M., Stougie, Leen, Bartlett, Karen H., Voelz, Kerstin, Pryszcz, Leszek P., Castañeda, Elizabeth, Lazera, Marcia, Meyer, Wieland, Deforce, Dieter, Meis, Jacques F., May, Robin C., Klaassen, Corné H. W., Boekhout, Teun·2013·PLoS ONE
DOI 10.1371/journal.pone.0071148PMC PMC3737135
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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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Figure 1 Coalescence gene genealogy based on SCAR-MLST data. The historical coalescence gene genealogy of the global Cryptococcus gattii AFLP6/VGII population structure was reconstructed by using five nuclear SCAR-MLST loci from which homoplasious sites were removed resulting in a total number of 109 informative sites indicated on the branches as blue (‘Fragment 15′ locus), orange (‘Fragment 32′ locus), green (‘Fragment 34′ locus), red (‘Fragment 54′ locus) and purple (IGS1 locus) dots. Numbers next to these dots represents the position of the site within the sequence of informative sites (Table S1). Haplotypes that represent lineages currently involved in outbreaks or case cluster are indicated along the lines of these haplotypes. Numbers behind the populations indicate the number of strains within the given population/haplotypes. Mouse virulence and IPR results are shown as red or green mice and macrophages, respectively, to represent virulent and non-virulent strains as indicated in Fig. 4 and 5, and Table 1 and S3. The ‘generation time to the most common recent ancestor’ (GTMRCA) in ‘generations before present’ is provided (bold), including the lower and upper boundaries.
Figure 1 Coalescence gene genealogy based on SCAR-MLST data. The historical coalescence gene genealogy of the global Cryptococcus gattii AFLP6/VGII population structure was reconstructed by using five nuclear SCAR-MLST loci from which homoplasious sites were removed resulting in a total number of 109 informative sites indicated on the branches as blue (‘Fragment 15′ locus), orange (‘Fragment 32′ locus), green (‘Fragment 34′ locus), red (‘Fragment 54′ locus) and purple (IGS1 locus) dots. Numbers next to these dots represents the position of the site within the sequence of informative sites (Table S1). Haplotypes that represent lineages currently involved in outbreaks or case cluster are indicated along the lines of these haplotypes. Numbers behind the populations indicate the number of strains within the given population/haplotypes. Mouse virulence and IPR results are shown as red or green mice and macrophages, respectively, to represent virulent and non-virulent strains as indicated in Fig. 4 and 5, and Table 1 and S3. The ‘generation time to the most common recent ancestor’ (GTMRCA) in ‘generations before present’ is provided (bold), including the lower and upper boundaries.CC BY · PubMed Central
Figure 2 Unrooted Maximum Likelihood phylogenetic analysis of the concatenated SCAR-MLST dataset. The STs corresponding to haplotypes H17, H24, H27 and H28, being the ancestral lineages in the coalescence gene genealogy analysis, were found to be the most basal lineages when rooted with C. gattii AFLP4. Populations are indicated as AFR (Africa), AUS (Australasia), EUR (Europe), NA (North America) and SA (South America), followed by symbols indicating clinical (), environmental (♣) and/or veterinary (•) strains within the given ST. The most ancestral lineage H17 is indicated by a tree to highlight its environmental origin from a tree in pristine Amazon rainforest in Northern Brazil. STs that fell into H01 as the major genotype AFLP6A/VGIIa Vancouver Island outbreak lineage, H02 as the case cluster of C. gattii infections among psittacine birds in Brazil, H03 the minor genotype Vancouver Island outbreak lineage (ST4 and ST5), and the recently emerged genotype AFLP6C/VGIIc outbreak in the Pacific Northwest (ST39) are indicated with symbols referring to their respective origin (e.g. human referring to human infections, cat representing veterinary cases, dolphin representing infections among sea animals) (Fig. 1; Table 1 and S3). Bootstrap values are given for branches that are highly supported (≥75).
Figure 2 Unrooted Maximum Likelihood phylogenetic analysis of the concatenated SCAR-MLST dataset. The STs corresponding to haplotypes H17, H24, H27 and H28, being the ancestral lineages in the coalescence gene genealogy analysis, were found to be the most basal lineages when rooted with C. gattii AFLP4. Populations are indicated as AFR (Africa), AUS (Australasia), EUR (Europe), NA (North America) and SA (South America), followed by symbols indicating clinical (), environmental (♣) and/or veterinary (•) strains within the given ST. The most ancestral lineage H17 is indicated by a tree to highlight its environmental origin from a tree in pristine Amazon rainforest in Northern Brazil. STs that fell into H01 as the major genotype AFLP6A/VGIIa Vancouver Island outbreak lineage, H02 as the case cluster of C. gattii infections among psittacine birds in Brazil, H03 the minor genotype Vancouver Island outbreak lineage (ST4 and ST5), and the recently emerged genotype AFLP6C/VGIIc outbreak in the Pacific Northwest (ST39) are indicated with symbols referring to their respective origin (e.g. human referring to human infections, cat representing veterinary cases, dolphin representing infections among sea animals) (Fig. 1; Table 1 and S3). Bootstrap values are given for branches that are highly supported (≥75).CC BY · PubMed Central
Figure 3 Population sizes and global migration patterns of C. gattii. The C. gattii AFLP6/VGII populations Africa (orange), Australasia (blue), Europe (purple), North America (green) and South America (red) are indicated, together with their mean population size (θ; Table S2), by similar coloured ellipses. Bi-directional historical mean migration rates are provided for each of the population combinations (Table S2). The approximate geographical location of the most basal lineage of coalescence gene genealogy (H17) is indicated with a tree in the Amazon. The outbreaks in North America are indicated with icons of human, cat and dolphin, and the parrot in the South American population indicates the case cluster of C. gattii infections among psittacine birds in Southern Brazil. Yellow coloured areas in the map represent localities with a Mediterranean climate according to the updated Köppen-Geigen classification (adapted from [37]).
Figure 3 Population sizes and global migration patterns of C. gattii. The C. gattii AFLP6/VGII populations Africa (orange), Australasia (blue), Europe (purple), North America (green) and South America (red) are indicated, together with their mean population size (θ; Table S2), by similar coloured ellipses. Bi-directional historical mean migration rates are provided for each of the population combinations (Table S2). The approximate geographical location of the most basal lineage of coalescence gene genealogy (H17) is indicated with a tree in the Amazon. The outbreaks in North America are indicated with icons of human, cat and dolphin, and the parrot in the South American population indicates the case cluster of C. gattii infections among psittacine birds in Southern Brazil. Yellow coloured areas in the map represent localities with a Mediterranean climate according to the updated Köppen-Geigen classification (adapted from [37]).CC BY · PubMed Central
Figure 4 Pathogenicity based on macrophage J774 Intracellular Proliferation Rate (IPR) and survival of BALB/c mice. The fifty percent survival time (ST50) in days for BALB/c mice infected with C. gattii is presented on the x-axis and plotted against the Intracellular Proliferation Rate (IPR) of the same C. gattii strain inside murine J774 macrophage cells. Strains that were not virulent in the BALB/c mice experiment after 45 days are excluded from this graph (A1M-R272, IPR = 0.88; CBS1930, IPR = 1.14; CBS7750, IPR = 0.93; CBS8684, IPR = 0.90; and IHEM11489, IPR = 1.77). The origins of the strains are indicated as AFR (Africa), AUS (Australasia), EUR (Europe), NA (North America) and SA (South America). For detailed IPR and ST50 survival values see Table S3.
Figure 4 Pathogenicity based on macrophage J774 Intracellular Proliferation Rate (IPR) and survival of BALB/c mice. The fifty percent survival time (ST50) in days for BALB/c mice infected with C. gattii is presented on the x-axis and plotted against the Intracellular Proliferation Rate (IPR) of the same C. gattii strain inside murine J774 macrophage cells. Strains that were not virulent in the BALB/c mice experiment after 45 days are excluded from this graph (A1M-R272, IPR = 0.88; CBS1930, IPR = 1.14; CBS7750, IPR = 0.93; CBS8684, IPR = 0.90; and IHEM11489, IPR = 1.77). The origins of the strains are indicated as AFR (Africa), AUS (Australasia), EUR (Europe), NA (North America) and SA (South America). For detailed IPR and ST50 survival values see Table S3.CC BY · PubMed Central
Figure 5 BALB/c mice survival curves. The Kaplan-Meier survival curves for each of the BALB/c mice virulence experiments carried out with 22 strains as listed from highest to lowest virulence potential in mice based on the ST50 values (Fig. 4; Table 1 and S3). Strains that showed identical progression of survival have similar curve profiles. The number of included mice per test are indicated between brackets, an asterisk after the strain number indicates that the data was from a previous mice virulence study [19]. Next to the strain number, the ST50, macrophage IPR and the coalescence gene genealogy haplotype number (H) are provided (Fig. 1; Table 1 and S3), followed by a symbol indicating a clinical (), environmental (♣) or veterinary (•) origin of the strain, as well as the population to which the strain belongs (AFR = Africa; AUS = Australasia; EUR = Europe; NA = North America; SA = South America). Note that strains A1M-R272, CBS1930, CBS7750, CBS8684 and IHEM11489 are non-virulent until day 45.
Figure 5 BALB/c mice survival curves. The Kaplan-Meier survival curves for each of the BALB/c mice virulence experiments carried out with 22 strains as listed from highest to lowest virulence potential in mice based on the ST50 values (Fig. 4; Table 1 and S3). Strains that showed identical progression of survival have similar curve profiles. The number of included mice per test are indicated between brackets, an asterisk after the strain number indicates that the data was from a previous mice virulence study [19]. Next to the strain number, the ST50, macrophage IPR and the coalescence gene genealogy haplotype number (H) are provided (Fig. 1; Table 1 and S3), followed by a symbol indicating a clinical (), environmental (♣) or veterinary (•) origin of the strain, as well as the population to which the strain belongs (AFR = Africa; AUS = Australasia; EUR = Europe; NA = North America; SA = South America). Note that strains A1M-R272, CBS1930, CBS7750, CBS8684 and IHEM11489 are non-virulent until day 45.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Griffiths A (2006) M.Sc. thesis ‘Assessing exposure to Cryptococcus gattii’, University of British Columbia, Vancouver, BC, Canada. Available: https://circle.ubc.ca/handle/2429/17839. Accessed 4 July 2013.

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Metadata

Authors
Hagen, F., Ceresini, P. C., Polacheck, I., Ma, H., Nieuwerburgh, F. V., Gabaldón, T., Kagan, S., Pursall, E. R., Hoogveld, H. L., van Iersel, L. J. J., Klau, G. W., Kelk, S. M., Stougie, L., Bartlett, K. H., Voelz, K., Pryszcz, L. P., Castañeda, E., Lazera, M., Meyer, W., Deforce, D., Meis, J. F., May, R. C., Klaassen, C. H. W., & Boekhout, T.
Affiliations
  • Westerdijk Fungal Biodiversity Institute (NL)
  • Universidade Estadual Paulista (Unesp) (BR)
  • Hadassah Medical Center (IL)
  • University of Birmingham (GB)
  • Ghent University (BE)
  • Centre for Genomic Regulation (ES)
  • Netherlands Institute of Ecology (NL)
  • Centrum Wiskunde & Informatica (NL)
  • University of British Columbia (CA)
  • Instituto Nacional de Salud (CO)
  • The University of Sydney (AU)
  • Radboud University Medical Center (NL)
  • Canisius-Wilhelmina Ziekenhuis (NL)
  • Second Military Medical University (CN)
Corresponding author
Boekhout, Teun
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-08-07
Volume
8
Issue
8
Pages
e71148
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0071148
PMC
PMC3737135
OpenAlex
W2152772772
Cited by
218
References
42
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 28 · 2020: 18 · 2019: 14 · 2018: 19 · 2017: 33 · 2016: 21 · 2015: 27 · 2014: 30 · 2013: 4
FWCI
19.92
Type
journal article
Language
en
Open access
Licence
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Funders
  • Qatar Foundation
  • Fonds National de la Recherche Luxembourg
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Qatar National Research Fund
Topics
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Pathogens and Fungal Diseases
Keywords
Cryptococcus gattii, fungal outbreak, human fungal infections, Amazon rainforest, population dispersal, recombination, phylogenetics, multilocus sequence typing, Northern Brazil, fungal genotypes
MeSH terms
Animals, Brazil, British Columbia, Cells, Cultured, Cryptococcosis, Disease Outbreaks, Genes, Fungal, Humans, Macrophages, Mice, Inbred BALB C, Molecular Sequence Data, Phylogeny, Polymorphism, Restriction Fragment Length, Trees, Tropical Climate, Virulence, Northwestern United States, Likelihood Functions, Mycological Typing Techniques, Mice, Cryptococcus gattii, Multilocus Sequence Typing

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