Global Control of Aspergillus fumigatus Toxins Nancy Keller University of Wisconsin

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Global Control of Aspergillus fumigatus Toxins Nancy Keller University of Wisconsin Slide 2 Aspergillus secondary metabolites Slide 3 Aspergillus laeA: transcriptional regulator of secondary metabolite genes Bok and Keller, Euk Cell, 3: 527-535 ST WT laeA A. nidulans GT WT laeA comp A. fumigatus Slide 4 Time (Days) 02468 0 20 40 60 80 100 laeA Wild type 02468 20 40 60 80 100 02468 20 40 60 80 100 Survival % 02468 20 40 60 80 10 0 Complemented Mouse survival LaeA is a virulence factor in Aspergillus fumigatus Bok et al, Euk Cell, 4:1574-1582 51560 0 10 20 30 40 50 60 WT laeA Incubation (minutes) PMN death (%) Macrophage phagocytosis WT laeA Neutrophil death Slide 5 Slide 6 Gardiner and Howlett 2005, Microbiology Slide 7 Number of conidia (10 6 /ml/cm 2 ) 0 10 20 30 40 50 60 WT gliZ gliZ + gliZ A. fumigatus gliZ grows at same rate, produces same number of spores Slide 8 Gt WT gliZ + gliZ gliZ + gliZ laeA gliZ does not produce gliotoxin Slide 9 gliZ regulates other genes in the gliotoxin gene cluster gliZ rRNA 36hr 72hr WT laeA gliZ gliZcom gliI A B 0.5 kb 1.0 kb 1 2 3 4 Slide 10 Murine pulmonary model Slide 11 Gliotoxin standard Non-infected lung gliZ laeA WT 1000 5.005.205.405.605.806.006.206.406.606.807.007.20 Time (min) 0 0 17 0 520 0 19 0 312 0 92 5.87 5.80 5.87 Gliotoxin chromatograms lung tissue gliZ + gliZ Slide 12 A B p=0.04 0 5 10 15 20 25 30 35 40 45 WT laeA gliZ gliZcom8.3 PI + (% PMNs) 0 10 20 30 40 50 60 Annexin + (% PMNs) WT laeA gliZ gliZcom8.3 Slide 13 Acknowledgements Keller Lab Dr. JinWoo Bok Elyse Bolterstein Dr. Marion Brodhagen DaWoon Chung Tom Hammond Lane Milde Dr. Robyn Perrin James Scott E. Keats Shwab 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

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