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Global Control of Aspergillus fumigatus Toxins

Global Control of Aspergillus fumigatus Toxins. Nancy Keller University of Wisconsin. Aspergillus secondary metabolites. Aspergillus laeA: transcriptional regulator of secondary metabolite genes. A. fumigatus. A. nidulans. ST WT  laeA. GT WT  laeA comp.

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Global Control of Aspergillus fumigatus Toxins

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  1. Global Control of Aspergillus fumigatus Toxins Nancy Keller University of Wisconsin

  2. Aspergillus secondary metabolites

  3. AspergilluslaeA: transcriptional regulator of secondary metabolite genes A. fumigatus A. nidulans ST WT laeA GT WT laeAcomp Bok and Keller, Euk Cell, 3: 527-535

  4. Macrophage phagocytosis WT DlaeA 60 WT 50 DlaeA 40 PMN death (%) 30 20 10 0 5 15 60 Incubation (minutes) LaeA is a virulence factor in Aspergillus fumigatus Mouse survival 100 100 100 100 80 80 80 80 Survival % 60 60 60 60 Neutrophil death 40 40 40 40 DlaeA 20 20 20 20 Wild type Complemented 0 0 0 0 0 2 2 2 2 4 4 4 4 6 6 6 6 8 8 8 8 Time (Days) Bok et al, Euk Cell, 4:1574-1582

  5. Gardiner and Howlett 2005, Microbiology

  6. A. fumigatus DgliZ grows at same rate, produces same number of spores 60 Number of conidia (106/ml/cm2) 50 40 30 20 10 0 WT DgliZ DgliZ + gliZ DgliZ + gliZ

  7. DgliZ does not produce gliotoxin DlaeA DgliZ + gliZ Gt DgliZ + gliZ WT DgliZ

  8. gliZ regulates other genes in the gliotoxin gene cluster B A 1 2 3 4 36hr 72hr WT DlaeA DgliZ DgliZcom WT DlaeA DgliZ DgliZcom gliZ gliI 1.0 kb 0.5 kb rRNA

  9. 100 100 100 100 80 80 80 80 60 60 60 60 Survival (%) 40 40 40 40 WT DlaeA 20 20 20 20 DgliZ DgliZcom8.3 0 0 0 0 0 0 0 0 2 2 2 2 4 4 4 4 6 6 6 6 8 8 8 8 Time (Days post infection) Murine pulmonary model

  10. Gliotoxin chromatograms lung tissue 5.87 92 DlaeA 0 5.80 312 WT 0 19 DgliZ 0 5.87 520 DgliZ + gliZ 0 17 Non-infected lung 0 5.87 1000 Gliotoxin standard 0 5.00 5.20 5.40 5.60 5.80 6.00 6.20 6.40 6.60 6.80 7.00 7.20 Time (min)

  11. A 45 40 35 30 25 PI + (% PMNs) 20 15 10 5 0 DlaeA DgliZ DgliZcom8.3 WT p=0.04 B p=0.04 60 50 40 30 Annexin + (% PMNs) 20 10 0 DlaeA DgliZ DgliZcom8.3 WT

  12. Acknowledgements • Collaborators • Drs. Bill Nierman, Natalie Fedorova • The Institute for Genomic Research (microarrays) • Dr. David Andes • Department of Medicine, Section of Infectious Disease, UW Madison • Drs. Kieren Marr and Arunmozhi Balajee • Fred Hutchinson Cancer Research Center • Drs. Jens Frisvad & Kristian Fog Nielsen • Department of Biotechnology, Technical University of Denmark • Keller Lab • Dr. JinWoo Bok • Elyse Bolterstein • Dr. Marion Brodhagen • DaWoon Chung • Tom Hammond • Lane Milde • Dr. Robyn Perrin • James Scott • E. Keats Shwab

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