Invasive Hyphal Growth in Wangiella dermatitidis Is Induced by Stab Inoculation and Shows Dependence upon Melanin Biosynthesis

Brush, Lisa D.; Money, Nicholas P.

doi:10.1006/fgbi.1999.1176

Cited by 58 publications

(39 citation statements)

References 37 publications

(47 reference statements)

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“…These multiple functions may help explain the pathogenic potential of some dematiaceous fungi, even in immunocompetent hosts. Specifically, in E. dermatitidis, disruption of melanin production leads to markedly reduced virulence in animal models and restriction of hyphal growth (103,201,203,428). However, hyphae of S. prolificans were found to be more susceptible to damage from neutrophils than A. fumigatus (284).…”

Section: Role Of Melaninmentioning

confidence: 99%

Melanized Fungi in Human Disease

2010

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SUMMARY Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections.

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Section: Role Of Melaninmentioning

confidence: 99%

Melanized Fungi in Human Disease

2010

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“…Brush and Money hypothesized that melanized hyphae exert larger turgor-derived forces at their apices than nonmelanized cells in W. dermatitidis, explaining their propensity for fast substrate invasion (5).…”

Section: Vol 69 2001mentioning

confidence: 99%

Molecular Cloning and Characterization of WdPKS1 , a Gene Involved in Dihydroxynaphthalene Melanin Biosynthesis and Virulence in Wangiella ( Exophiala ) dermatitidis

et al. 2001

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1,8-Dihydroxynaphthalene (1,8-DHN) is a fungal polyketide that contributes to virulence when polymerized to 1,8-DHN melanin in the cell walls of Wangiella dermatitidis, an agent of phaeohyphomycosis in humans.To begin a genetic analysis of the initial synthetic steps leading to 1,8-DHN melanin biosynthesis, a 772-bp PCR product was amplified from genomic DNA using primers based on conserved regions of fungal polyketide synthases (Pks) known to produce the first cyclized 1,8-DHN-melanin pathway intermediate, 1,3,6,8-tetrahydroxynaphthalene. The cloned PCR product was then used as a targeting sequence to disrupt the putative polyketide synthase gene, WdPKS1, in W. dermatitidis. The resulting wdpks1⌬ disruptants showed no morphological defects other than an albino phenotype and grew at the same rate as their black wild-type parent. Using a marker rescue approach, the intact WdPKS1 gene was then successfully recovered from two plasmids. The WdPKS1 gene was also isolated independently by complementation of the mel3 mutation in an albino mutant of W. dermatitidis using a cosmid library. Sequence analysis substantiated that WdPKS1 encoded a putative polyketide synthase (WdPks1p) in a single open reading frame consisting of three exons separated by two short introns. This conclusion was supported by the identification of highly conserved Pks domains for a ␤-ketoacyl synthase, an acetyl-malonyl transferase, two acyl carrier proteins, and a thioesterase in the deduced amino acid sequence. Studies using a neutrophil killing assay and a mouse acute-infection model confirmed that all wdpks1⌬ strains were less resistant to killing and less virulent, respectively, than their wild-type parent. Reconstitution of 1,8-DHN melanin biosynthesis in a wdpks1⌬ strain reestablished its resistance to killing by neutrophils and its ability to cause fatal mouse infections.The zoopathogenic fungus Wangiella (Exophiala) dermatitidis is one of many form species of the Fungi Imperfecti, which are darkly pigmented (dematiaceous) owing to the deposition of 1,8-dihydroxynaphthalene (1,8-DHN) melanin in their cell walls (22,45). This fungus has recently become better known as a paradigm for the causative agents of phaeohyphomycosis and other emerging dermatomycoses of humans, because of its increasing detection as a systemic pathogen in both immunocompetent and immunocompromised patients (34, 35). Moreover, because W. dermatitidis has a well-defined polymorphic nature and a well-characterized cell wall chemistry, it serves as an excellent model for the more than 100 other dematiaceous fungal pathogens of humans (14,37,42).Although dark pigments of fungi are often called melanin without regard to mode of enzymatic synthesis or chemical composition, most syntheses of melanin are attributed to either a phenoloxidase, e.g., laccases and tyrosinases, or a polyketide synthase (Pks) of a pentaketide biosynthetic pathway (52). The phenoloxidases have been found mostly among basidiomycete fungi and are usually composed of soluble enzymes with broad substra...

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“…In contrast, sclerotic cells of W. dermatitidis are isotropically enlarged, nonpolarized morphotypes that may become internally partitioned with one septum to produce planate cells or multiple intersecting septa to produce sclerotic bodies. Because all the growth forms of this polymorphic fungus have also been observed in infected host tissues, W. dermatitidis is increasingly used as a model for gaining insights into the biology of the more than one hundred other dematiaceous pathogenic fungi (Brush and Money, 1999;Matsumoto et al, 1994;Szaniszlo, 2006).…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of WdTUP1, a gene that encodes a potential transcriptional repressor important for yeast-hyphal transitions in Wangiella (Exophiala) dermatitidis

Liu

Abramczyk

Cooper

et al. 2008

Fungal Genetics and Biology

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The general transcriptional repressor Tup1p is known to influence cell development in many fungi. To determine whether the Tup1p ortholog (WdTup1p) of Wangiella dermatitidis also influences cellular development in this melanized, polymorphic human pathogen, the gene (WdTUP1) that encodes this transcription factor was isolated, sequenced and disrupted. Phylogenetic analysis showed that the WdTup1p sequence was closely related to homologues in other polymorphic, conidiogenous fungi. Disruption of WdTUP1 produced mutants (wdtup1Δ) with pronounced growth and cellular abnormalities, including slow growth on various agar media and exclusively as a filamentous morphotype in liquid media. We concluded that WdTup1p represents an important switch regulator that controls the yeast-to-filamentous growth transition. However, detailed observations of the filamentous growth of the disruption mutant showed that the hyphae produced by the wdtup1Δ mutants, unlike those of the wild type, were arrested at a stage prior to the formation of true hyphae and subsequent conidia production.

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Invasive Hyphal Growth in Wangiella dermatitidis Is Induced by Stab Inoculation and Shows Dependence upon Melanin Biosynthesis

Cited by 58 publications

References 37 publications

Melanized Fungi in Human Disease

Melanized Fungi in Human Disease

Molecular Cloning and Characterization of WdPKS1 , a Gene Involved in Dihydroxynaphthalene Melanin Biosynthesis and Virulence in Wangiella ( Exophiala ) dermatitidis

Molecular cloning and characterization of WdTUP1, a gene that encodes a potential transcriptional repressor important for yeast-hyphal transitions in Wangiella (Exophiala) dermatitidis

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