Aspergillus fumigatus is a serious medical menace and ranks as the most severe filamentous mold causing human disease with 60% overall reported fatality. The increasing population of susceptible immunocompromised individuals coupled with the rising incidence of antifungal resistant fungal isolates underscore the need for new diagnostic and therapeutic modalities. Identification of fungal and host molecules suitable for diagnostic or therapy development is the major goal of this proposal. Compiling data from genomic studies of A. fumigatus/host interactions, we have uncovered 30 A. fumigatus transcription factors (TFs) critical for the two fungal morphologies important in disease development: spores required for initial infection and hyphae, the form of the fungus growing invasively in vivo.
Aim 1 thus focuses on identification of spore armaments and fungal/host crosstalk in initial host encounters mediated by spore specific TFs.
Aim 2 characterizes the fungal TFs and host molecules enabling invasive hyphal growth in vivo. Simultaneously to Aims 1 and 2, Aim 3 will develop state-of-the-art microfluidic platforms that allow, for the first time, screening of 1000s of A. fumigatus mutants for invasive growth properties and host activation of A. fumigatus virulence proteins. This latter aim is critical for the Aspergillus research community due to the relative ease of generating A. fumigatus mutants and the pipeline availability of a complete A. fumigatus genome knockout library (10,000 genes);screening of this many mutants renders animal studies a major roadblock in assessment of A. fumigatus virulence factors. Indeed, the study of Aspergillus host interactions has been limited by the lack of available robust platforms that (i) enable visualization of intimate fungal/host interactions, (ii) allow for rapid assessment of virulence traits or (iii) evaluate the role of fungal and host signaling molecules that are difficult to obtain in large enough quantities for macrostudies.
Aim 3 will provide these platforms to help the research community meet the needs of the Aspergillus genomic era.
Aspergillus fumigatus is a serious medical menace and ranks as the most severe filamentous mold causing human disease associated with unacceptably high mortality. The worldwide frequency and the profile of patients at risk for invasive aspergillosis (IA) continues to expand, owing to increased numbers of immunocompromised patients including those afflicted with HIV/AIDS, malignancy, leukemia and organ dysfunction. This fungus can cause additional morbidity associated with sinusitis, asthma, and allergic bronchopulmonary aspergillosis in non-immunosuppressed people.
|Soukup, Alexandra A; Keller, Nancy P; Wiemann, Philipp (2016) Enhancing Nonribosomal Peptide Biosynthesis in Filamentous Fungi. Methods Mol Biol 1401:149-60|
|Barkal, Layla J; Theberge, Ashleigh B; Guo, Chun-Jun et al. (2016) Microbial metabolomics in open microscale platforms. Nat Commun 7:10610|
|Throckmorton, Kurt; Lim, Fang Yun; Kontoyiannis, Dimitrios P et al. (2016) Redundant synthesis of a conidial polyketide by two distinct secondary metabolite clusters in Aspergillus fumigatus. Environ Microbiol 18:246-59|
|Wang, Pin-Mei; Choera, Tsokyi; Wiemann, Philipp et al. (2016) TrpE feedback mutants reveal roadblocks and conduits toward increasing secondary metabolism in Aspergillus fumigatus. Fungal Genet Biol 89:102-13|
|Kerr, Sheena C; Fischer, Gregory J; Sinha, Meenal et al. (2016) FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection. PLoS Pathog 12:e1005555|
|Keller, Nancy P (2015) Translating biosynthetic gene clusters into fungal armor and weaponry. Nat Chem Biol 11:671-7|
|Lim, Fang Yun; Keller, Nancy P (2014) Spatial and temporal control of fungal natural product synthesis. Nat Prod Rep 31:1277-86|
|Wiemann, Philipp; Lechner, Beatrix E; Baccile, Joshua A et al. (2014) Perturbations in small molecule synthesis uncovers an iron-responsive secondary metabolite network in Aspergillus fumigatus. Front Microbiol 5:530|
|Lim, Fang Yun; Ames, Brian; Walsh, Christopher T et al. (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 16:1267-83|
|Yin, Wen-Bing; Baccile, Joshua A; Bok, Jin Woo et al. (2013) A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J Am Chem Soc 135:2064-7|
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