Systematic Genetic Analysis of Virulence in the Human Fungal Pathogen Cryptococcus neoformans

Liu, Oliver W.; Chun, Cheryl D.; Chow, Eric D.; Chen, Changbin; Madhani, Hiten D.

doi:10.1016/j.cell.2008.07.046

Cited by 406 publications

(585 citation statements)

References 47 publications

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“…However, there was no consistent difference between VIO and non-VIO isolates belonging to this genotype in any of the traits tested, suggesting that the virulence of VIO strains does not simply result from over-expression of these individual cryptococcal pathogenicity factors. Such a finding is consistent with recent data suggesting that many cryptococcal virulence genes/factors remain to be discovered (13).…”

Section: Hypervirulence Of Vio Strains Is Not Directly Linked To Any supporting

confidence: 82%

“…Interestingly, although our phenotypic analysis demonstrated that no single known virulence factor was responsible for the hypervirulence of the VIO isolates, several of these genes (e.g., PLB1, CRG1, capsule related genes, and genes on the mating type locus,) showed a significant expression correlation with IPR, suggesting that they may synergistically contribute to virulence within the AFLP6 lineage. Notably, some of our uncharacterised candidate genes were also recently identified by Liu et al as influencing melanin and capsule production and, thus, cryptococcal infectivity (e.g., COP9 signalosome complex and ubiquitin carboxyl-terminal hydrolase) (13).…”

Section: Identification Of Genes Associated With Enhanced Intracellulmentioning

confidence: 99%

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The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

Hagen²,

Stekel³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

176

217

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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.cryptococcus ͉ macrophage ͉ Vancouver Island outbreak ͉ virulence

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Section: Hypervirulence Of Vio Strains Is Not Directly Linked To Any supporting

confidence: 82%

Section: Identification Of Genes Associated With Enhanced Intracellulmentioning

confidence: 99%

The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

Hagen²,

Stekel³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

176

217

View full text Add to dashboard Cite

show abstract

“…Through these combined bioinformatic analyses, we therefore identified a total of seven possible GATA factor-encoding genes. Of the seven predicted GATA ORFs identified, all four previously characterized C. neoformans members of this family were present: Bwc2, Cir1, Gat201, and Gat1-thus validating the combination approach taken Jung et al 2006;Liu et al 2008; Figure 2.-Nitrogen metabolite repression influences capsule and melanin formation. (A) India ink cell staining under light microscopy showed that wild-type H99 produces capsules that vary in size when grown on YNB supplemented with different nitrogen sources (10 mm each).…”

Section: Resultsmentioning

confidence: 97%

Nitrogen Metabolite Repression of Metabolism and Virulence in the Human Fungal Pathogen Cryptococcus neoformans

et al. 2011

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Proper regulation of metabolism is essential to maximizing fitness of organisms in their chosen environmental niche. Nitrogen metabolite repression is an example of a regulatory mechanism in fungi that enables preferential utilization of easily assimilated nitrogen sources, such as ammonium, to conserve resources. Here we provide genetic, transcriptional, and phenotypic evidence of nitrogen metabolite repression in the human pathogen Cryptococcus neoformans. In addition to loss of transcriptional activation of catabolic enzyme-encoding genes of the uric acid and proline assimilation pathways in the presence of ammonium, nitrogen metabolite repression also regulates the production of the virulence determinants capsule and melanin. Since GATA transcription factors are known to play a key role in nitrogen metabolite repression, bioinformatic analyses of the C. neoformans genome were undertaken and seven predicted GATA-type genes were identified. A screen of these deletion mutants revealed GAT1, encoding the only global transcription factor essential for utilization of a wide range of nitrogen sources, including uric acid, urea, and creatinine-three predominant nitrogen constituents found in the C. neoformans ecological niche. In addition to its evolutionarily conserved role in mediating nitrogen metabolite repression and controlling the expression of catabolic enzyme and permease-encoding genes, Gat1 also negatively regulates virulence traits, including infectious basidiospore production, melanin formation, and growth at high body temperature (39°-40°). Conversely, Gat1 positively regulates capsule production. A murine inhalation model of cryptococcosis revealed that the gat1D mutant is slightly more virulent than wild type, indicating that Gat1 plays a complex regulatory role during infection.

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“…This raises the possibility that the ER is a sensor of elevated temperature in C. neoformans. Interestingly, a recent signature-tagged mutagenesis (STM) study of systematic gene knockouts in C. neoformans revealed that a mutant with the conserved UPR mediator IRE1 deleted was decreased an average of 10-fold relative to the input in the STM screen, with the ire1⌬ strain exhibiting a growth defect at host temperature (20). Our data suggest that IRE1 function is intact in our ccr4⌬ mutant, as ER stress transcripts are induced during a shift to host temperature as in the wild type, again suggesting that the role of Ccr4 is in the downregulation or attenuation of the ER stress response.…”

Section: Discussionmentioning

confidence: 99%

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

et al. 2011

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Adaptation to host temperature is a prerequisite for any pathogen capable of causing deep infection in humans. Our previous studies demonstrated that a Cryptococcus neoformans ccr4⌬ mutant lacking the major deadenylase involved in regulated mRNA decay was defective in host temperature adaptation and therefore virulence. In this study, the ccr4⌬ mutant was found to exhibit characteristics of chronic unfolded-protein response (UPR) engagement in both the gene expression profile and phenotype. We demonstrate that host temperature adaptation in C. neoformans is accompanied by transient induction of the endoplasmic reticulum (ER) stress response and that Ccr4-dependent posttranscriptional gene regulation contributes to resolution of ER stress during host temperature adaptation.The pathogenic fungus Cryptococcus neoformans is one of two species of cryptococci commonly associated with infection in humans (2, 6). Unifying characteristics of the pathogenic cryptococci include the production of a polysaccharide capsule, the ability to form melanin pigments through the activity of the multicopper oxidase laccase, and the ability to adapt to and thrive at mammalian host temperature. Adaptation of C. neoformans to the host temperature is accompanied by major changes in gene expression as measured by microarray analysis and serial analysis of gene expression (SAGE) (5,19,29). This modulation of gene expression likely requires alterations in mRNA synthesis rates through activation of transcriptional transactivators and repressors, as well as alterations in chromatin structure. In addition to mRNA synthesis, our previous studies of a C. neoformans ccr4⌬ mutant lacking the major mRNA deadenylase involved in regulated mRNA turnover suggest a role for posttranscriptional regulation of gene expression in C. neoformans host temperature adaptation (24).Destabilization of specific transcripts in response to stress is highly conserved. In the model yeast Saccharomyces cerevisiae, deletion of CCR4 results in stabilization of transcripts encoding distinct functional classes (ribosome biogenesis, translation initiation, and tRNA synthesis) in response to temperature stress (13). In mammalian cells, subsets of transcripts were destabilized in response to heat shock, and induction of endoplasmic reticulum (ER) stress by treatment with tunicamycin or potentiation of ER calcium release by thapsigargin treatment triggered destabilization of a subset of mRNAs in which are included several transcripts encoding ribosomal proteins (8). This suggests that in response to heat shock and ER stress, distinct pools of transcripts representing specific cellular processes are targeted for degradation.The conserved ER stress response involves engagement of the unfolded-protein response (UPR) and the ER-associated degradation (ERAD) pathway (18). The UPR serves to retool the ER for enhanced protein folding, and ERAD serves to remove unfolded proteins from the ER lumen and shunt them into a degradative pathway. Microarray analyses performed in S. cerevisiae ...

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Systematic Genetic Analysis of Virulence in the Human Fungal Pathogen Cryptococcus neoformans

Cited by 406 publications

References 47 publications

The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

Nitrogen Metabolite Repression of Metabolism and Virulence in the Human Fungal Pathogen Cryptococcus neoformans

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

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