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

Ma, Hansong; Hagen, Ferry; Stekel, Dov J.; Johnston, Simon A.; Sionov, Edward; Falk, Rama; Polacheck, Itzhack; Boekhout, Teun; May, Robin C.

doi:10.1073/pnas.0902963106

Cited by 177 publications

(242 citation statements)

References 43 publications

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“…The discovery of sexual reproduction is significant, because mating could potentially result in recombinant strains with increased virulence. This phenomenon has been reported in other human fungal pathogens such as Cryptococcus gattii, which is responsible for an ongoing outbreak in the Pacific Northwest of the United States and Canada (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Discovery of a phenotypic switch regulating sexual mating in the opportunistic fungal pathogen Candida tropicalis

Porman

Alby

Hirakawa

et al. 2011

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

111

151

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Sexual reproduction can promote genetic diversity in eukaryotes, and yet many pathogenic fungi have been labeled as obligate asexual species. It is becoming increasingly clear, however, that cryptic sexual programs may exist in some species, and that efficient mating requires the necessary developmental switch to be triggered. In this study we investigate Candida tropicalis, an important human fungal pathogen that has been reported to be asexual. Significantly, we demonstrate that C. tropicalis uses a phenotypic switch to regulate a cryptic program of sexual mating. Thus, diploid a and α cells must undergo a developmental transition to the mating-competent form, and only then does efficient cell-cell conjugation take place resulting in the formation of stable a/α tetraploids. We show that both the phenotypic switch and sexual mating depend on the conserved transcriptional regulator Wor1, which is regulated by temperature in other fungal species. In contrast, C. tropicalis mating occurs efficiently at both 25°C and 37°C, suggesting that it could occur in the mammalian host and have direct consequences for the outcome of an infection. Transcriptional profiling further reveals that ≈400 genes are differentially expressed between the two phenotypic states, including the regulatory factor Wor1. Taken together, our results demonstrate that C. tropicalis has a unique sexual program, and that entry to this program is controlled via a Wor1-mediated, metastable switch. These observations have direct implications for the regulation and evolution of cryptic sexual programs in related fungal pathogens.epigenetic | recombination | bistability

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Section: Discussionmentioning

confidence: 99%

Discovery of a phenotypic switch regulating sexual mating in the opportunistic fungal pathogen Candida tropicalis

Porman

Alby

Hirakawa

et al. 2011

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

111

151

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“…Taken together, these associations, in the HIV-infected host, are indicative of a host environment with inactivated phagocytes (37) due to a paucity of IFN-γ, in which the easily phagocytosed cryptococcal strains thrive and proliferate, resulting in a greater fungal burden. This is in contrast to C. gattii infection in the immunocompetent host, in which a strong adaptive immune response results in appropriate macrophage activation and in which the ability to rapidly replicate in macrophages is likely to be more important for virulence (16). In HIV-infected patients with CM, we propose that the ease of uptake of cryptococci by macrophages, coupled with the inability to orchestrate an effective IFN-γ-activated fungicidal macrophage response, results in unchecked proliferation and survival of the fungus, with dissemination to the CNS yielding high fungal burden.…”

Section: Figurementioning

confidence: 94%

“…In Cryptococcus gattii infections of immunocompetent hosts, intracellular proliferation within phagocytes correlates with virulence in a murine model of cryptococcosis (16). Using a large patient-matched set of clinical isolates and the established murine macrophage-like cell line J774 (see Table 1 for a summary of patient baseline characteristics, isolate genotype, and in vitro phenotype), we tested whether a similar relationship exists for C. neoformans, but found no significant correlation between the intracellular proliferation rate (IPR) and patient fungal burden upon presentation (Spearman's rank correlation r = -0.2, P = 0.22).…”

Section: High Cryptococcal Uptake By Macrophages Is Associated With Hmentioning

confidence: 99%

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Sabiiti¹,

Robertson²,

Beale³

et al. 2014

J. Clin. Invest.

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134

173

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Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis.Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis.Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003).Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccasedependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM.

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“…For example, the Group 1 and 2 regulators cooperate to induce mitochondrially encoded respiration genes, resulting in massive up-regulation of these genes (mean, 57-fold; median, 20-fold). This is interesting because host conditions are hypoxic (Erecinska and Silver 2001), and the virulence of Cryptococcus gatii, which can cause fatal infections in immunocompetent individuals, is closely associated with up-regulation of mitochondrial gene expression (Ma et al 2009). We also integrated our broad analysis of transcriptional dynamics with our focused analysis of nucleotide sugar regulation.…”

Section: Discussionmentioning

confidence: 99%

Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation

et al. 2015

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Key steps in understanding a biological process include identifying genes that are involved and determining how they are regulated. We developed a novel method for identifying transcription factors (TFs) involved in a specific process and used it to map regulation of the key virulence factor of a deadly fungus-its capsule. The map, built from expression profiles of 41 TF mutants, includes 20 TFs not previously known to regulate virulence attributes. It also reveals a hierarchy comprising executive, midlevel, and "foreman" TFs. When grouped by temporal expression pattern, these TFs explain much of the transcriptional dynamics of capsule induction. Phenotypic analysis of TF deletion mutants revealed complex relationships among virulence factors and virulence in mice. These resources and analyses provide the first integrated, systems-level view of capsule regulation and biosynthesis. Our methods dramatically improve the efficiency with which transcriptional networks can be analyzed, making genomic approaches accessible to laboratories focused on specific physiological processes.[Supplemental material is available for this article.]In this paper we present an efficient means of comprehensively mapping the network of transcription factors (TFs) that regulate a particular physiological process. Our approach cycles through deletion of TFs, expression profiling of TF mutants, model construction, and model-directed selection of TFs for the next round of deletion. This predictive genetics approach identifies TFs that affect the process of interest, providing a valuable complement to undirected mutagenesis and screening. Simultaneously, it builds a network model that explains how the TFs affect the process, yielding novel insights into the biological system under study.Mapping the network that regulates a specific process requires knowing which TFs affect that process. One way to identify such TFs is to screen comprehensive mutant libraries, but generating such libraries is not always feasible. Furthermore, genome-scale screening assays must be fast and scalable; such assays may not exist for the process of interest or may be less sensitive than other, more laborious assays. An alternative approach is to map the targets of all TFs encoded in a genome by using methods such as chromatin-immunoprecipitation (ChIP) or large-scale TF deletion and expression analysis. However, undirected, genome-wide approaches are costly and inefficient for probing a specific biological process in detail. We report a model-guided approach that addresses all of these problems by focusing experimental effort on the TFs most likely to be involved in the process of interest. Furthermore, our approach generates a network that provides mechanistic explanations for the phenotypes of TF deletion mutants.Our approach alternates network building by using an algorithm we call NetProphet with identifying relevant TFs by using an algorithm we call PhenoProphet. NetProphet is a validated method for mapping direct, functional regulation that significantly out...

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

Cited by 177 publications

References 43 publications

Discovery of a phenotypic switch regulating sexual mating in the opportunistic fungal pathogen Candida tropicalis

Discovery of a phenotypic switch regulating sexual mating in the opportunistic fungal pathogen Candida tropicalis

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation

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