NANCY KELLER, PHD

Research

The long-term goal of my research program is to reduce aflatoxin and sterigmatocystin contamination of food and feed crops. Aflatoxin (AF) and sterigmatocystin (ST) are toxic and carcinogenic secondary metabolites produced by the same biochemical pathway in several Aspergillus spp. My program focuses on identifying the molecular genetic processes controlling expression of ST/AF biosynthesis and host metabolites which effect fungal growth and ST/AF biosynthesis. Results from these areas of research are directed towards designing rational ST/AF control strategies and should contribute to control of other fungal pathogens.

We are using A. nidulans to dissect the molecular mechanisms governing genetic control of ST biosynthesis. We have isolated a ST gene cluster in A. nidulans and have identified gene functions within the cluster through gene disruption and sequence analysis. This cluster contains 26 genes encoding both enzymatic activities and regulatory proteins necessary for ST and AF biosynthesis. We have demonstrated that both regulatory and structural genes are conserved between the A. nidulans ST gene cluster and the A. flavus and A. parasiticus AF gene clusters. Most interestingly, we find that both sporulation and mycotoxin biosynthesis are inactivated by the same Ga protein-dependent signaling pathway thus suggesting the possibility of a strategy to control inoculum and ST/AF production simultaneously.

We are also interested in host factors which affect the regulation of mycotoxin production in Aspergillus spp. and have identified linoleic acid-derived compounds from the lipoxygenase pathway of plants which regulate both fungal sporulation and ST/AF production. One current goal involves transforming corn and peanut plants with a soybean lipoxygenase gene whose product inhibited AF/ST biosynthesis in laboratory studies. Ultimately, many of our studies should lead to creating transgenic crops where AF/ST-inducing or inhibiting traits will be engineered ‘out’ or ‘into’ plants respectively.

These studies will be complemented by functional genomic projects where we are involved in sequencing the Aspergillus genome and analyzing Aspergillus/seed ESTs. Microarray analysis of host seed and Aspergillus genes should reveal those set required for pathogenesis and aflatoxin production in situ.

Publications

• Zheng H, Kim J, Liew M, Yan JK, Herrera O, Bok JW, Kelleher NL, Keller NP, Wang Y (2015) Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus. Curr. Biol. 25(1):29-37
• Zhao Y, Xi Q, Xu Q, He M, Ding J, Dai Y, Keller NP, Zheng W (2015) Correlation of nitric oxide produced by an inducible nitric oxide synthase-like protein with enhanced expression of the phenylpropanoid pathway in Inonotus obliquus cocultured with Phellinus morii. Appl. Microbiol. Biotechnol.
• Macheleidt J, Scherlach K, Neuwirth T, Schmidt-Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Hertweck C, Heinekamp T, Brakhage AA (2015) Transcriptome analysis of cyclic AMP-dependent protein kinase A-regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus. Mol. Microbiol.
• Bok JW, Wiemann P, Garvey GS, Lim FY, Haas B, Wortman J, Keller NP (2014) Illumina identification of RsrA, a conserved C2H2 transcription factor coordinating the NapA mediated oxidative stress signaling pathway in Aspergillus. BMC Genomics 15:1011
• Wiemann P, Lechner BE, Baccile JA, Velk TA, Yin WB, Bok JW, Pakala S, Losada L, Nierman WC, Schroeder FC, Haas H, Keller NP (2014) Perturbations in small molecule synthesis uncovers an iron-responsive secondary metabolite network in Aspergillus fumigatus. Front Microbiol 5:530
• Knox BP, Deng Q, Rood M, Eickhoff JC, Keller NP, Huttenlocher A (2014) Distinct innate immune phagocyte responses to Aspergillus fumigatus conidia and hyphae in zebrafish larvae. Eukaryotic Cell 13(10):1266-77
• Lim FY, Keller NP (2014) Spatial and temporal control of fungal natural product synthesis. Nat Prod Rep 31(10):1277-86
• canonical Aspergillus flavus G protein-coupled receptors. MBio 5(5):e01501-14
• Lim FY, Ames B, Walsh CT, Keller NP (2014) Co-ordination between BrlA regulation and secretion of the oxidoreductase FmqD directs selective accumulation of fumiquinazoline C to conidial tissues in Aspergillus fumigatus. Cell. Microbiol. 16(8):1267-83
• Miyamoto K, Murakami T, Kakumyan P, Keller NP, Matsui K (2014) Formation of 1-octen-3-ol from Aspergillus flavus conidia is accelerated after disruption of cells independently of Ppo oxygenases, and is not a main cause of inhibition of germination. PeerJ 2:e395
• Amare MG, Keller NP (2014) Molecular mechanisms of Aspergillus flavus secondary metabolism and development. Fungal Genet. Biol. 66:11-8
• Spraker JE, Jewell K, Roze LV, Scherf J, Ndagano D, Beaudry R, Linz JE, Allen C, Keller NP (2014) A volatile relationship: profiling an inter-kingdom dialogue between two plant pathogens, Ralstonia Solanacearum and Aspergillus Flavus. J. Chem. Ecol. 40(5):502-13
• Wiemann P, Keller NP (2014) Strategies for mining fungal natural products. J. Ind. Microbiol. Biotechnol. 41(2):301-13

Mentor to METC Post-Docs:

• Graeme Garvey (2008-2010);
• Marion Brodhagen (2006)