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

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.

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The interplay between iron and zinc metabolism in Aspergillus fumigatus

Fungal Genetics and Biology ◽

10.1016/j.fgb.2009.05.003 ◽

2009 ◽

Vol 46 (9) ◽

pp. 707-713 ◽

Cited By ~ 22

Author(s):

Sabiha Yasmin ◽

Beate Abt ◽

Markus Schrettl ◽

Tarek A.A. Moussa ◽

Ernst R. Werner ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Zinc Metabolism ◽

Iron And Zinc

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The effect of moderately increased intakes of complex carbohydrates (cereals, vegetables and fruit) for 12 weeks on iron and zinc metabolism

British Journal Of Nutrition ◽

10.1079/bjn19900146 ◽

1990 ◽

Vol 63 (3) ◽

pp. 597-611 ◽

Cited By ~ 15

Author(s):

Pamela M. Manson ◽

Patricia A. Judd ◽

Susan J. Fairweather-Tait ◽

John Eagles ◽

Margret J. Minski

Keyword(s):

Adverse Effect ◽

Bowel Function ◽

Zinc Metabolism ◽

Moderate Increase ◽

Adult Women ◽

Zinc Absorption ◽

Zn Nutrition ◽

Iron And Zinc ◽

Complex Carbohydrates ◽

Zn Status

Fifteen adult women were given diets in which the intake of complex carbohydrates was increased from 20 to 30 g over a 12 week period. Metabolic balances were carried out, iron and zinc absorption tests performed using stable isotopes, and Fe and Zn status monitored. Although effects on bowel function were observed, the changed diet had no influence on any of the previously described variables. It was concluded that a moderate increase in cereals, fruit and vegetables did not have an adverse effect on Fe or Zn nutrition.

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Entry into the stationary phase is associated with a rapid loss of viability and an apoptotic-like phenotype in the opportunistic pathogen Aspergillus fumigatus

Fungal Genetics and Biology ◽

10.1016/s1087-1845(03)00047-1 ◽

2003 ◽

Vol 39 (3) ◽

pp. 221-229 ◽

Cited By ~ 52

Author(s):

S.Amin A. Mousavi ◽

Geoffrey D. Robson

Keyword(s):

Stationary Phase ◽

Aspergillus Fumigatus ◽

Opportunistic Pathogen ◽

Rapid Loss

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

Applied and Environmental Microbiology ◽

10.1128/aem.07249-11 ◽

2012 ◽

Vol 78 (9) ◽

pp. 3166-3176 ◽

Cited By ~ 33

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.

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Effect of Intestinal Microflora on Iron and Zinc Metabolism, and on Activities of Metalloenzymes in Rats

Journal of Nutrition ◽

10.1093/jn/102.1.101 ◽

1972 ◽

Vol 102 (1) ◽

pp. 101-107 ◽

Cited By ~ 19

Author(s):

Bandaru S. Reddy ◽

Julian R. Pleasants ◽

Bernard S. Wostmann

Keyword(s):

Intestinal Microflora ◽

Zinc Metabolism ◽

Iron And Zinc

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

Eukaryotic Cell ◽

10.1128/ec.5.1.212-215.2006 ◽

2006 ◽

Vol 5 (1) ◽

pp. 212-215 ◽

Cited By ~ 199

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.

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Genetic Diversity and Dispersal of Aspergillus fumigatus in Arctic Soils

Genes ◽

10.3390/genes13010019 ◽

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.

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

Frontiers in Microbiology ◽

10.3389/fmicb.2020.563139 ◽

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.

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

Journal of Fungi ◽

10.3390/jof6040258 ◽

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.

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