Global Control of Aspergillus fumigatus Toxins Nancy Keller University of Wisconsin

Aspergillus secondary metabolites

Aspergillus laeA: transcriptional regulator of secondary metabolite genes Bok and Keller, Euk Cell, 3: ST WT laeA A. nidulans GT WT laeA comp A. fumigatus

Time (Days) laeA Wild type Survival % Complemented Mouse survival LaeA is a virulence factor in Aspergillus fumigatus Bok et al, Euk Cell, 4: WT laeA Incubation (minutes) PMN death (%) Macrophage phagocytosis WT laeA Neutrophil death

Gardiner and Howlett 2005, Microbiology

Number of conidia (10 6 /ml/cm 2 ) WT gliZ gliZ + gliZ A. fumigatus gliZ grows at same rate, produces same number of spores

Gt WT gliZ + gliZ gliZ + gliZ laeA gliZ does not produce gliotoxin

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

Murine pulmonary model

Gliotoxin standard Non-infected lung gliZ laeA WT Time (min) Gliotoxin chromatograms lung tissue gliZ + gliZ

A B p= WT laeA gliZ gliZcom8.3 PI + (% PMNs) Annexin + (% PMNs) WT laeA gliZ gliZcom8.3

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