A multigene family related to chitin synthase genes of yeast in the opportunistic pathogen Aspergillus fumigatus

1995 ◽  
Vol 246 (3) ◽  
pp. 353-359 ◽  
Author(s):  
Emilia Mellado ◽  
Agnès Aufauvre-Brown ◽  
Charles A. Specht ◽  
Phillips W. Robbins ◽  
David W. Holden
Keyword(s):  
Aspergillus Fumigatus ◽  
Multigene Family ◽  
Opportunistic Pathogen ◽  
Chitin Synthase

scholarly journals Nitrogen, Iron and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence

2021 ◽  
Vol 7 (7) ◽  
pp. 518
Author(s):  
Uxue Perez-Cuesta ◽  
Xabier Guruceaga ◽  
Saioa Cendon-Sanchez ◽  
Eduardo Pelegri-Martinez ◽  
Fernando L. Hernando ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Zinc Metabolism ◽  
Wide Field ◽  
Regulation Process ◽  
Number Of Genes ◽  
Iron And Zinc ◽  
Fungal Nutrition

Aspergillus fumigatus is a ubiquitous soil decomposer and an opportunistic pathogen that is characterized by its large metabolic machinery for acquiring nutrients from media. Lately, an ever-increasing number of genes involved in fungal nutrition has been associated with its virulence. Of these, nitrogen, iron, and zinc metabolism-related genes are particularly noteworthy, since 78% of them have a direct implication in virulence. In this review, we describe the sensing, uptake and regulation process of the acquisition of these nutrients, the connections between pathways and the virulence-implicated genes. Nevertheless, only 40% of the genes mentioned in this review have been assayed for roles in virulence, leaving a wide field of knowledge that remains uncertain and might offer new therapeutic and diagnostic targets.

scholarly journals Transcriptional Regulation of Chitin Synthases by Calcineurin Controls Paradoxical Growth of Aspergillus fumigatus in Response to Caspofungin

2010 ◽  
Vol 54 (4) ◽  
pp. 1555-1563 ◽  
Author(s):  
Jarrod R. Fortwendel ◽  
Praveen R. Juvvadi ◽  
B. Zachary Perfect ◽  
Luise E. Rogg ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Laboratory Strain ◽  
Chitin Synthase ◽  
High Dose ◽  
Paradoxical Effect ◽  
Paradoxical Response ◽  
Paradoxical Growth ◽  
High Concentrations ◽  
Calcineurin Signaling

ABSTRACT Attenuated activity of echinocandin antifungals at high concentrations, known as the “paradoxical effect,” is a well-established phenomenon in Candida albicans and Aspergillus fumigatus. In the yeast C. albicans, upregulation of chitin biosynthesis via the protein kinase C (PKC), high-osmolarity glycerol response (HOG), and Ca2+/calcineurin signaling pathways is an important cell wall stress response that permits growth in the presence of high concentrations of echinocandins. However, nothing is known of the molecular mechanisms regulating the mold A. fumigatus and its paradoxical response to echinocandins. Here, we show that the laboratory strain of A. fumigatus and five of seven clinical A. fumigatus isolates tested display various magnitudes of paradoxical growth in response to caspofungin. Interestingly, none of the eight strains showed paradoxical growth in the presence of micafungin or anidulafungin. Treatment of the ΔcnaA and ΔcrzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent. Exploring a molecular role for CnaA in the compensatory chitin biosynthetic response, we found that caspofungin treatment resulted in increased chitin synthase gene expression, leading to a calcineurin-dependent increase in chitin synthase activity. Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment.

scholarly journals Nonribosomal Peptide Synthetase GenespesLandpes1Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

2012 ◽  
Vol 78 (9) ◽  
pp. 3166-3176 ◽  
Author(s):  
Karen A. O'Hanlon ◽  
Lorna Gallagher ◽  
Markus Schrettl ◽  
Christoph Jöchl ◽  
Kevin Kavanagh ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Mass Spectrometry Analysis ◽  
Infection Model ◽  
Nonribosomal Peptide ◽  
Content Type ◽  
Spectrometry Analysis ◽  
Peptide Synthetases ◽  
Increased Sensitivity

ABSTRACTThe identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen,Aspergillus fumigatus, remains outstanding. We found that the nonribosomal peptide (NRP) synthetases PesL and Pes1 were essential for fumigaclavine C biosynthesis, the end product of the complex ergot alkaloid (EA) pathway inA. fumigatus. Deletion of eitherpesL(ΔpesL) orpes1(Δpes1) resulted in complete loss of fumigaclavine C biosynthesis, relatively increased production of fumitremorgins such as TR-2, fumitremorgin C and verruculogen, increased sensitivity to H2O2, and increased sensitivity to the antifungals, voriconazole, and amphotericin B. Deletion ofpesLresulted in severely reduced virulence in an invertebrate infection model (P< 0.001). These findings indicate that NRP synthesis plays an essential role in mediating the final prenylation step of the EA pathway, despite the apparent absence of NRP synthetases in the proposed EA biosynthetic cluster forA. fumigatus. Liquid chromatography/diode array detection/mass spectrometry analysis also revealed the presence of fumiquinazolines A to F in bothA. fumigatuswild-type and ΔpesLstrains. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, since PesL has been shown to mediate fumiquinazoline biosynthesisin vitro. Furthermore, we provide here the first direct link between EA biosynthesis and virulence, in agreement with the observed toxicity associated with EA exposure. Finally, we demonstrate a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.

scholarly journals Gene Targeting in Aspergillus fumigatus by Homologous Recombination Is Facilitated in a Nonhomologous End- Joining-Deficient Genetic Background

2006 ◽  
Vol 5 (1) ◽  
pp. 212-215 ◽  
Author(s):  
Sven Krappmann ◽  
Christoph Sasse ◽  
Gerhard H. Braus
Keyword(s):  
Homologous Recombination ◽  
Aspergillus Fumigatus ◽  
Gene Targeting ◽  
Mutant Strain ◽  
Genetic Background ◽  
Opportunistic Pathogen ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Gene Encoding

ABSTRACT The akuA gene encoding the Ku70 component of the nonhomologous end-joining machinery was deleted in the opportunistic pathogen Aspergillus fumigatus. No obvious phenotype could be assessed for the corresponding mutant strain but relative frequencies of homologous recombination were increased as deduced from targeting the laccase-encoding abr2 gene.

scholarly journals Genetic Diversity and Dispersal of Aspergillus fumigatus in Arctic Soils

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 19
Author(s):  
Gregory A. Korfanty ◽  
Mykaelah Dixon ◽  
Haoran Jia ◽  
Heather Yoell ◽  
Jianping Xu
Keyword(s):  
Genetic Diversity ◽  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Ecological Niches ◽  
Ecological Distribution ◽  
Resistant Genotype ◽  
Arctic Regions ◽  
Arctic Soils ◽  
The World ◽  
Geographic Regions

Aspergillus fumigatus is a saprophytic mold and an opportunistic pathogen with a broad geographic and ecological distribution. A. fumigatus is the most common etiological agent of aspergillosis, affecting over 8,000,000 individuals worldwide. Due to the rising number of infections and increasing reports of resistance to antifungal therapy, there is an urgent need to understand A. fumigatus populations from local to global levels. However, many geographic locations and ecological niches remain understudied, including soil environments from arctic regions. In this study, we isolated 32 and 52 A. fumigatus strains from soils in Iceland and the Northwest Territories of Canada (NWT), respectively. These isolates were genotyped at nine microsatellite loci and the genotypes were compared with each other and with those in other parts of the world. Though significantly differentiated from each other, our analyses revealed that A. fumigatus populations from Iceland and NWT contained evidence for both clonal and sexual reproductions, and shared many alleles with each other and with those collected from across Europe, Asia, and the Americas. Interestingly, we found one triazole-resistant strain containing the TR34 /L98H mutation in the cyp51A gene from NWT. This strain is closely related to a triazole-resistant genotype broadly distributed in India. Together, our results suggest that the northern soil populations of A. fumigatus are significantly influenced by those from other geographic regions.

scholarly journals tpo3 and dur3, Aspergillus fumigatus Plasma Membrane Regulators of Polyamines, Regulate Polyamine Homeostasis and Susceptibility to Itraconazole

2020 ◽  
Vol 11 ◽  
Author(s):  
Mingcong Chen ◽  
Guowei Zhong ◽  
Sha Wang ◽  
Jun Zhu ◽  
Lei Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasma Membrane ◽  
Aspergillus Fumigatus ◽  
Drug Transport ◽  
Opportunistic Pathogen ◽  
Moderate Increase ◽  
High Concentration ◽  
Polyamine Biosynthesis ◽  
Drastic Increase ◽  
Polyamine Content

Aspergillus fumigatus is a well-known opportunistic pathogen that causes invasive aspergillosis (IA) infections, which have high mortality rates in immunosuppressed individuals. Long-term antifungal drug azole use in clinical treatment and agriculture results in loss of efficacy or drug resistance. Drug resistance is related to cellular metabolites and the corresponding gene transcription. In this study, through untargeted metabolomics and transcriptomics under itraconazole (ITC) treatment, we identified two plasma membrane-localized polyamine regulators tpo3 and dur3, which were important for polyamine homeostasis and susceptibility to ITC in A. fumigatus. In the absence of tpo3 and/or dur3, the levels of cytoplasmic polyamines had a moderate increase, which enhanced the tolerance of A. fumigatus to ITC. In comparison, overexpression of tpo3 or dur3 induced a drastic increase in polyamines, which increased the sensitivity of A. fumigatus to ITC. Further analysis revealed that polyamines concentration-dependently affected the susceptibility of A. fumigatus to ITC by scavenging reactive oxygen species (ROS) at a moderate concentration and promoting the production of ROS at a high concentration rather than regulating drug transport. Moreover, inhibition of polyamine biosynthesis reduced the intracellular polyamine content, resulted in accumulation of ROS and enhanced the antifungal activity of ITC. Interestingly, A. fumigatus produces much lower levels of ROS under voriconazole (VOC) treatment than under ITC-treatment. Accordingly, our study established the link among the polyamine regulators tpo3 and dur3, polyamine homeostasis, ROS content, and ITC susceptibility in A. fumigatus.

scholarly journals Global Sexual Fertility in the Opportunistic Pathogen Aspergillus fumigatus and Identification of New Supermater Strains

2020 ◽  
Vol 6 (4) ◽  
pp. 258
Author(s):  
Sameira S. Swilaiman ◽  
Céline M. O’Gorman ◽  
Wenyue Du ◽  
Janyce A. Sugui ◽  
Joanne Del Buono ◽  
...  
Keyword(s):  
Genetic Variation ◽  
High Temperature ◽  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Sexual Cycle ◽  
Mating Types ◽  
Irish Population ◽  
Mating Partner ◽  
Ascospore Germination ◽  
Temperature Heat

A sexual cycle in Aspergillus fumigatus was first described in 2009 with isolates from Dublin, Ireland. However, the extent to which worldwide isolates can undergo sexual reproduction has remained unclear. In this study a global collection of 131 isolates was established with a near 1:1 ratio of mating types. All isolates were crossed to MAT1-1 or MAT1-2 Irish strains, and a subset of isolates from different continents were crossed together. Ninety seven percent of isolates were found to produce cleistothecia with at least one mating partner, showing that sexual fertility is not limited to the Irish population but is a characteristic of global A. fumigatus. However, large variation was seen in numbers of cleistothecia produced per cross, suggesting differences in the possibility for genetic exchange between strains in nature. The majority of crosses produced ascospores with >50% germination rates, but with wide variation evident. A high temperature heat shock was required to induce ascospore germination. Finally, a new set of highly fertile MAT1-1 and MAT1-2 supermater strains were identified and pyrimidine auxotrophs generated for community use. Results provide insights into the potential for the A. fumigatus sexual cycle to generate genetic variation and allow gene flow of medically important traits.

scholarly journals Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies

2015 ◽  
Vol 59 (10) ◽  
pp. 5932-5941 ◽  
Author(s):  
Louise A. Walker ◽  
Keunsook K. Lee ◽  
Carol A. Munro ◽  
Neil A. R. Gow
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Dynamic Imaging ◽  
Chitin Synthase ◽  
Response To Treatment ◽  
Chitin Synthesis ◽  
Calcofluor White ◽  
Content Type ◽  
Chitin Content

ABSTRACTTreatment ofAspergillus fumigatuswith echinocandins such as caspofungin inhibits the synthesis of cell wall β-1,3-glucan, which triggers a compensatory stimulation of chitin synthesis. Activation of chitin synthesis can occur in response to sub-MICs of caspofungin and to CaCl2and calcofluor white (CFW), agonists of the protein kinase C (PKC), and Ca2+-calcineurin signaling pathways.A. fumigatusmutants with thechsgene (encoding chitin synthase) deleted (ΔAfchs) were tested for their response to these agonists to determine the chitin synthase enzymes that were required for the compensatory upregulation of chitin synthesis. Only the ΔAfchsGmutant was hypersensitive to caspofungin, and all other ΔAfchsmutants tested remained capable of increasing their chitin content in response to treatment with CaCl2and CFW and caspofungin. The resulting increase in cell wall chitin content correlated with reduced susceptibility to caspofungin in the wild type and all ΔAfchsmutants tested, with the exception of the ΔAfchsGmutant, which remained sensitive to caspofungin.In vitroexposure to the chitin synthase inhibitor, nikkomycin Z, along with caspofungin demonstrated synergistic efficacy that was againAfChsG dependent. Dynamic imaging using microfluidic perfusion chambers demonstrated that treatment with sub-MIC caspofungin resulted initially in hyphal tip lysis. However, thickened hyphae emerged that formed aberrant microcolonies in the continued presence of caspofungin. In addition, intrahyphal hyphae were formed in response to echinocandin treatment. Thesein vitrodata demonstrate thatA. fumigatushas the potential to survive echinocandin treatmentin vivobyAfChsG-dependent upregulation of chitin synthesis. Chitin-rich cells may, therefore, persist in human tissues and act as the focus for breakthrough infections.

scholarly journals Genetic and virulence variation in an environmental population of the opportunistic pathogen Aspergillus fumigatus

Microbiology ◽  
2014 ◽  
Vol 160 (4) ◽  
pp. 742-751 ◽  
Author(s):  
Fadwa Alshareef ◽  
Geoffrey D. Robson
Keyword(s):  
Aspergillus Fumigatus ◽  
Galleria Mellonella ◽  
Rapd Analysis ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Environmental Isolates ◽  
Pathogenic Potential ◽  
Patient Infection ◽  
Selection Of ◽  
Virulence Variation

Environmental populations of the opportunistic pathogen Aspergillus fumigatus have been shown to be genotypically diverse and to contain a range of isolates with varying pathogenic potential. In this study, we combined two RAPD primers to investigate the genetic diversity of environmental isolates from Manchester collected monthly over 1 year alongside Dublin environmental isolates and clinical isolates from patients. RAPD analysis revealed a diverse genotype, but with three major clinical isolate clusters. When the pathogenicity of clinical and Dublin isolates was compared with a random selection of Manchester isolates in a Galleria mellonella larvae model, as a group, clinical isolates were significantly more pathogenic than environmental isolates. Moreover, when relative pathogenicity of individual isolates was compared, clinical isolates were the most pathogenic, Dublin isolates were the least pathogenic and Manchester isolates showed a range in pathogenicity. Overall, this suggests that the environmental population is genetically diverse, displaying a range in pathogenicity, and that the most pathogenic strains from the environment are selected during patient infection.

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