Abstract
Human and animal cryptococcosis due to an unusual molecular type of Cryptococcus gattii (VGII) emerged recently on Vancouver Island, Canada. Unlike C. neoformans, C. gattii causes disease mainly in immunocompetent hosts, despite producing a similar suite of virulence determinants. To investigate a potential relationship between the regulation of expression of a virulence gene composite and virulence, we took advantage of two subtypes of VGII (a and b), one highly virulent (R265) and one less virulent (R272), that were identified from the Vancouver outbreak. By expression microarray analysis, 202 genes showed at least a 2-fold difference in expression with 108 being up- and 94 being down-regulated in strain R265 compared with strain R272. Specifically, expression levels of genes encoding putative virulence factors (e.g. LAC1, LAC2, CAS3 and MPK1) and genes encoding proteins involved in cell wall assembly, carbohydrate and lipid metabolism were increased in strain R265, whereas genes involved in the regulation of mitosis and ergosterol biosynthesis were suppressed. In vitro phenotypic studies and transcription analysis confirmed the microarray results. Gene disruption of LAC1 and MPK1 revealed defects in melanin synthesis and cell wall integrity, respectively, where CAS3 was not essential for capsule production. Moreover, MPK1 also controls melanin and capsule production and causes a severe attenuation of the virulence in a murine inhalational model. Overall, this study provides the basis for further genetic studies to characterize the differences in the virulence composite of strains with minor evolutionary divergences in gene expression in the primary pathogen C. gattii, that have led to a major invasive fungal infection outbreak.
Highlights
The primary pathogen Cryptococcus gattii, previously designated as Cryptococcus bacillisporus or Cryptococcus neoformans var. gattii, is a basidiomycetous yeast that in Australia causes disease primarily in immunocompetent hosts [1]. It is a member of the Cryptococcus neoformans/C. gattii species complex [2]
An early study revealed that a strain (R265) of the predominant subtype in the outbreak (VGIIa), was more virulent for A/Jcr mice than an isolate (R272) of the minor subtype (VGIIb), the proposed parental strain of R265 [15]
These findings suggest that either these down-regulated genes are not involved in virulence expression directly or that the level of suppression is not sufficient to reduce the virulence of strain R265
Summary
The primary pathogen Cryptococcus gattii, previously designated as Cryptococcus bacillisporus or Cryptococcus neoformans var. gattii, is a basidiomycetous yeast that in Australia causes disease primarily in immunocompetent hosts [1]. Gattii, is a basidiomycetous yeast that in Australia causes disease primarily in immunocompetent hosts [1]. It is a member of the Cryptococcus neoformans/C. gattii species complex [2]. An early study revealed that a strain (R265) of the predominant subtype in the outbreak (VGIIa), was more virulent for A/Jcr mice than an isolate (R272) of the minor subtype (VGIIb), the proposed parental strain of R265 [15]. It was shown in a sample of 40 VGIIa and VGIIb strains from around the world that the VGIIa subtype produced more of the virulence determinant, melanin, than did the VGIIb subtype [16]. One-half of the gene sequences used as MLST markers in the R265 and R272 strains are identical [15]
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