Whole-Genome Analysis of Cryptococcus gattii, Southeastern United States.
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ABSTRACT:
SUBMITTER: Lockhart SR
PROVIDER: S-EPMC4880073 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Whole-Genome Analysis of Cryptococcus gattii, Southeastern United States.
Lockhart Shawn R SR Roe Chandler C CC Engelthaler David M DM
Emerging infectious diseases 20160601 6
Cryptococcus gattii is a recognized pathogenic fungus along the Pacific coast of the United States from California to Washington. Here we report that C. gattii may also be endemic to the southeastern United States and has probably been present there longer than in the Pacific Northwest. ...[more]
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Project description: Not available
| S-EPMC3358153 | biostudies-literature
Project description:A recent emergence of Cryptococcus gattii in the Pacific Northwest involves strains that fall into three primarily clonal molecular subtypes: VGIIa, VGIIb and VGIIc. Multilocus sequence typing (MLST) and variable number tandem repeat analysis appear to identify little diversity within these molecular subtypes. Given the apparent expansion of these subtypes into new geographic areas and their ability to cause disease in immunocompetent individuals, differentiation of isolates belonging to these subtypes could be very important from a public health perspective. We used whole genome sequence typing (WGST) to perform fine-scale phylogenetic analysis on 20 C. gattii isolates, 18 of which are from the VGII molecular type largely responsible for the Pacific Northwest emergence. Analysis both including and excluding (289,586 SNPs and 56,845 SNPs, respectively) molecular types VGI and VGIII isolates resulted in phylogenetic reconstructions consistent, for the most part, with MLST analysis but with far greater resolution among isolates. The WGST analysis presented here resulted in identification of over 100 SNPs among eight VGIIc isolates as well as unique genotypes for each of the VGIIa, VGIIb and VGIIc isolates. Similar levels of genetic diversity were found within each of the molecular subtype isolates, despite the fact that the VGIIb clade is thought to have emerged much earlier. The analysis presented here is the first multi-genome WGST study to focus on the C. gattii molecular subtypes involved in the Pacific Northwest emergence and describes the tools that will further our understanding of this emerging pathogen.
| S-EPMC3233577 | biostudies-literature
Project description:BackgroundCryptococcusgattii infections are being reported in the United States (US) with increasing frequency. Initially, US reports were primarily associated with an ongoing C. gattii outbreak in the Pacific Northwest (PNW) states of Washington and Oregon, starting in 2004. However, reports of C. gattii infections in patients from other US states have been increasing since 2009. Whether this is due to increasing frequency of disease, greater recognition within the clinical community, or both is currently unknown.Methodology/principal findingsDuring 2005-2013, a total of 273 C. gattii isolates from human and veterinary sources in 16 US states were collected. Of these, 214 (78%) were from the Pacific Northwest (PNW) and comprised primarily the clonal C. gattii genotypes VGIIa (64%), VGIIc (21%) and VGIIb (9%). The 59 isolates from outside the PNW were predominantly molecular types VGIII (44%) and VGI (41%). Genotyping using multilocus sequence typing revealed small clusters, including a cluster of VGI isolates from the southeastern US, and an unrelated cluster of VGI isolates and a large cluster of VGIII isolates from California. Most of the isolates were mating type MATα, including all of the VGII isolates, but one VGI and three VGIII isolates were mating type MATa.Conclusions/significanceWe provide the most comprehensive report to date of genotypic diversity of US C. gattii isolates both inside and outside of the PNW. C. gattii may have multiple endemic regions in the US, including a previously-unrecognized endemic region in the southeast. Regional clusters exist both in California and the Southeastern US. VGII strains associated with the PNW outbreak do not appear to have spread substantially beyond the PNW.
| S-EPMC3760847 | biostudies-literature
Project description:BACKGROUND: Cryptococcus gattii is a fungal pathogen causing an emerging outbreak in the United States Pacific Northwest (PNW). Treatment guidelines for cryptococcosis are primarily based on data from C. neoformans infections; applicability to PNW C. gattii infection is unknown. We evaluated the relationship between initial antifungal treatment and outcomes for PNW C. gattii patients. METHODS: Cases were defined as culture-confirmed invasive C. gattii infections among residents of Oregon and Washington States during 2004-2011. Clinical data were abstracted from medical records through one year of follow-up. Recommended initial treatment for central nervous system (CNS), bloodstream, and severe pulmonary infections is amphotericin B and 5-flucytosine; for non-severe pulmonary infections, recommended initial treatment is fluconazole. Alternative initial treatment was defined as any other initial antifungal treatment. RESULTS: Seventy patients survived to diagnosis; 50 (71%) received the recommended initial treatment and 20 (29%) received an alternative. Fewer patients with pulmonary infections [21 (64%)] than CNS infections [25 (83%)] received the recommended initial treatment (p = 0.07). Among patients with pulmonary infections, those with severe infections received the recommended initial treatment less often than those with non-severe infections (11% vs. 83%, p<0.0001). Eight patients with severe pulmonary infections received alternative initial treatments; three died. Four patients with non-severe pulmonary infections received alternative initial treatments; two died. There was a trend towards increased three-month mortality among patients receiving alternative vs. recommended initial treatment (30% vs. 14%, p = 0.12), driven primarily by increased mortality among patients with pulmonary disease receiving alternative vs. recommended initial treatment (42% vs. 10%, p = 0.07). CONCLUSIONS: C. gattii patients with pulmonary infections--especially severe infections--may be less likely to receive recommended treatment than those with CNS infections; alternative treatment may be associated with increased mortality. Reasons for receipt of alternative treatment among C. gattii patients in this area should be investigated, and clinician awareness of recommended treatment reinforced.
| S-EPMC3929541 | biostudies-other
Project description:Cryptococcus gattii causes life-threatening disease in otherwise healthy hosts and to a lesser extent in immunocompromised hosts. The highest incidence for this disease is on Vancouver Island, Canada, where an outbreak is expanding into neighboring regions including mainland British Columbia and the United States. This outbreak is caused predominantly by C. gattii molecular type VGII, specifically VGIIa/major. In addition, a novel genotype, VGIIc, has emerged in Oregon and is now a major source of illness in the region. Through molecular epidemiology and population analysis of MLST and VNTR markers, we show that the VGIIc group is clonal and hypothesize it arose recently. The VGIIa/IIc outbreak lineages are sexually fertile and studies support ongoing recombination in the global VGII population. This illustrates two hallmarks of emerging outbreaks: high clonality and the emergence of novel genotypes via recombination. In macrophage and murine infections, the novel VGIIc genotype and VGIIa/major isolates from the United States are highly virulent compared to similar non-outbreak VGIIa/major-related isolates. Combined MLST-VNTR analysis distinguishes clonal expansion of the VGIIa/major outbreak genotype from related but distinguishable less-virulent genotypes isolated from other geographic regions. Our evidence documents emerging hypervirulent genotypes in the United States that may expand further and provides insight into the possible molecular and geographic origins of the outbreak.
| S-EPMC2858702 | biostudies-literature
Project description:The emergence of distinct populations of Cryptococcus gattii in the temperate North American Pacific Northwest (PNW) was surprising, as this species was previously thought to be confined to tropical and semitropical regions. Beyond a new habitat niche, the dominant emergent population displayed increased virulence and caused primary pulmonary disease, as opposed to the predominantly neurologic disease seen previously elsewhere. Whole-genome sequencing was performed on 118 C. gattii isolates, including the PNW subtypes and the global diversity of molecular type VGII, to better ascertain the natural source and genomic adaptations leading to the emergence of infection in the PNW. Overall, the VGII population was highly diverse, demonstrating large numbers of mutational and recombinational events; however, the three dominant subtypes from the PNW were of low diversity and were completely clonal. Although strains of VGII were found on at least five continents, all genetic subpopulations were represented or were most closely related to strains from South America. The phylogenetic data are consistent with multiple dispersal events from South America to North America and elsewhere. Numerous gene content differences were identified between the emergent clones and other VGII lineages, including genes potentially related to habitat adaptation, virulence, and pathology. Evidence was also found for possible gene introgression from Cryptococcus neoformans var. grubii that is rarely seen in global C. gattii but that was present in all PNW populations. These findings provide greater understanding of C. gattii evolution in North America and support extensive evolution in, and dispersal from, South America. Importance: Cryptococcus gattii emerged in the temperate North American Pacific Northwest (PNW) in the late 1990s. Beyond a new environmental niche, these emergent populations displayed increased virulence and resulted in a different pattern of clinical disease. In particular, severe pulmonary infections predominated in contrast to presentation with neurologic disease as seen previously elsewhere. We employed population-level whole-genome sequencing and analysis to explore the genetic relationships and gene content of the PNW C. gattii populations. We provide evidence that the PNW strains originated from South America and identified numerous genes potentially related to habitat adaptation, virulence expression, and clinical presentation. Characterization of these genetic features may lead to improved diagnostics and therapies for such fungal infections. The data indicate that there were multiple recent introductions of C. gattii into the PNW. Public health vigilance is warranted for emergence in regions where C. gattii is not thought to be endemic.
| S-EPMC4161256 | biostudies-literature
Project description:Cryptococcus gattii emerged in North America in 1999 as a human and veterinary pathogen on Vancouver Island, British Columbia. The emergent subtype, VGIIa, and the closely related subtype VGIIb can now be found in the United States in Washington, Oregon, and California. We performed multilocus sequence typing and antifungal susceptibility testing on 43 isolates of C. gattii from human patients in Oregon, Washington, California, and Idaho. In contrast to Vancouver Island, VGIIa was the most frequent but not the predominant subtype in the northwest United States. Antifungal susceptibility testing showed statistically significant differences in MICs between the subtypes. This is the first study to apply antifungal susceptibility testing to C. gattii isolates from the Pacific Northwest and the first to make direct comparisons between subtypes.
| S-EPMC2815610 | biostudies-literature
Project description:We have developed a two-step method based on high-resolution melting (HRM) that reliably identifies species from the Cryptococcus species complex (Cryptococcus neoformans var. grubii, Cryptococcus neoformans var. neoformans, and Cryptococcus gattii). Our results indicate that HRM can provide a fast protocol to identify and distinguish among the main Cryptococcus species.
| S-EPMC3187306 | biostudies-literature
Project description:Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.
| S-EPMC3037005 | biostudies-literature
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