Aspergillus fumigatus is the major invasive mold pathogen of immunosuppressed patients, causing exceptionally high morbidity and mortality. Weakened defenses as a consequence of hematopoietic stem cell transplantation or solid organ transplantation allow growth of inhaled spores in the lung and dissemination. Both therapy and diagnosis are problematic, a situation that contributes to extremely high mortality rates. Our objective is to use A. fumigatus gene expression during infection in a murine model to define virulence genes. We will prioritize genes for functional analysis based on in vivo expression and host response, and then validate the utility of the data through construction of new mutant strains and determination of their virulence potential. These gene products in turn will be high priority targets for therapeutic and diagnostic development. We will use a nanoString nCounter to quantify specific A. fumigatus RNA levels in infected tissue. NanoString estimates of RNA levels are much more sensitive than microarray estimates or current RNA-Seq capability. Our proposed studies focus on three classes of gene products: transcription factors, surface and secreted proteins, and secondary metabolite biosynthetic enzymes. We have chosen transcription factor genes because their products can be connected to target genes and biological functions through expression profiling and chromatin immunoprecipitation. We have chosen surface and secreted protein genes because their products present the most accessible therapeutic targets, and because their possible release into fluids makes them candidate diagnostic targets. We have chosen secondary metabolite genes because their products may have biological activity, such as immunomodulation, that is relevant to pathogenesis. We will develop a reference dataset that explores expression of these genes, and extend the analysis with functional validation through two specific aims. First, we will define A. fumigatus gene expression during lung infection, using a murine model and two sequenced A. fumigatus strains. Second, we will validate functional inferences from expression data through virulence assays of select mutant strains. Our findings will significantly improve the understanding of A. fumigatus infection by providing a set of regulatory pathways, surface/secreted products, and toxins that impact infection. The information will be critical for prioritizing pathways and gene products as targets for therapeutic and diagnostic development, and to connect basic research studies to gene products that are highly relevant to infection.

Public Health Relevance

Our studies focus on Aspergillus fumigatus, a major pathogen of immunosuppressed patients. A. fumigatus infection often proves fatal, and improvements are needed in both therapy and diagnosis. We will define genes that A. fumigatus expresses and utilizes during invasive infection. Our analysis will point to genes that are high priority targetsfor development of therapies and diagnostic assays.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-IDM-M (02))
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Duncan, Rory A
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Carnegie-Mellon University
Schools of Arts and Sciences
United States
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Voltersen, Vera; Blango, Matthew G; Herrmann, Sahra et al. (2018) Proteome Analysis Reveals the Conidial Surface Protein CcpA Essential for Virulence of the Pathogenic Fungus Aspergillus fumigatus. MBio 9:
Guruceaga, Xabier; Ezpeleta, Guillermo; Mayayo, Emilio et al. (2018) A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus. Virulence 9:1548-1561
Liu, Hong; Xu, Wenjie; Solis, Norma V et al. (2018) Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity. Virulence 9:1062-1073
Xu, Wenjie; Solis, Norma V; Filler, Scott G et al. (2016) Gene Expression Profiling of Infecting Microbes Using a Digital Bar-coding Platform. J Vis Exp :e53460
Xu, Wenjie; Solis, Norma V; Filler, Scott G et al. (2016) Pathogen Gene Expression Profiling During Infection Using a Nanostring nCounter Platform. Methods Mol Biol 1361:57-65
Liu, Hong; Lee, Mark J; Solis, Norma V et al. (2016) Aspergillus fumigatus CalA binds to integrin ?5?1 and mediates host cell invasion. Nat Microbiol 2:16211
Lee, Mark J; Liu, Hong; Barker, Bridget M et al. (2015) The Fungal Exopolysaccharide Galactosaminogalactan Mediates Virulence by Enhancing Resistance to Neutrophil Extracellular Traps. PLoS Pathog 11:e1005187
Pongpom, Monsicha; Liu, Hong; Xu, Wenjie et al. (2015) Divergent targets of Aspergillus fumigatus AcuK and AcuM transcription factors during growth in vitro versus invasive disease. Infect Immun 83:923-33
Chung, Dawoon; Barker, Bridget M; Carey, Charles C et al. (2014) ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence. PLoS Pathog 10:e1004487