Cryptococcus gattii Virulence Composite: Candidate Genes Revealed by Microarray Analysis of High and Less Virulent Vancouver Island Outbreak Strains

Ngamskulrungroj, Popchai; Price, Jennifer L.; Sorrell, Tania C.; Perfect, John R.; Meyer, Wieland

doi:10.1371/journal.pone.0016076

Cited by 54 publications

(66 citation statements)

References 68 publications

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“…Some gene products, such as the capsule (134) and Plb1 (135,136), have been well characterized in C. gattii, but in few instances have deletion mutants or overexpressing strains been created and tested for virulence in animal models. An exception is the laccase gene LAC1, created in R265, the virulent VGIIa strain from the Vancouver Island outbreak, the overexpression of which was associated with increased virulence in a mouse inhalation model (137). In that same study, disruption of CAS1, which is associated with the construction of the polysaccharide capsule backbone in C. neoformans (138), did not affect capsule size but, when overexpressed, was associated with hypervirulence in mice.…”

Section: Cryptococcal Virulence Determinantsmentioning

confidence: 92%

“…Levels of proteins involved in cell wall assembly, membrane components, carbohydrate and lipid metabolism, transport, the stress response, and lignin degradation were all increased in the VGIIa strain, whereas genes involved in the regulation of mitosis, ergosterol biosynthesis, and drug resistance were downregulated (137). Differences in several other genes, including cell wall assembly and mitotic regulatory genes, were identified.…”

Section: Genomic and Transcriptomic Profilesmentioning

confidence: 95%

“…In that same study, disruption of CAS1, which is associated with the construction of the polysaccharide capsule backbone in C. neoformans (138), did not affect capsule size but, when overexpressed, was associated with hypervirulence in mice. Disruption of the signal transduction pathway molecule MPK1, which causes defective melanin synthesis and cell wall integrity, was associated with reduced virulence (137). Additional genes, transcription factors, and signaling molecules that have been linked to virulence in C. gattii are summarized in Table 3.…”

Section: Cryptococcal Virulence Determinantsmentioning

confidence: 99%

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Cryptococcus gattii Infections

2014

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SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

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Section: Cryptococcal Virulence Determinantsmentioning

confidence: 92%

Section: Genomic and Transcriptomic Profilesmentioning

confidence: 95%

Section: Cryptococcal Virulence Determinantsmentioning

confidence: 99%

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Cryptococcus gattii Infections

2014

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“…In airborne fungal spores, melanin helps in invasion of the host (3,4) and contributes to the virulence of fungal pathogens (5,6). Fungi produce different types of melanin: dihydroxynaphthalene (DHN)-melanin, pyomelanin, and DOPA-melanin.…”

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confidence: 99%

Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response

et al. 2014

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gIn Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface.

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“…However, it was the discovery of the natural habitat of C. gattii in 1990 14 that provided a major impetus for research on the epidemiology and ecology of this fungus. These studies defined the epidemiology of these serious fungal infections in Australia 15 and elsewhere and through global collaborations, have revealed the origin of highly pathogenic strains and increased understanding of the molecular basis of cryptococcal pathogenicity 16,17 .…”

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confidence: 99%