Invasive aspergillosis is one of the most feared diseases in the immunocompromised host, and its incidence is steadily increasing. Despite new therapies, the mortality of this disease is greater than 50%. A critical step in the pathogenesis o invasive aspergillosis is the interaction of Aspergillus fumigatus with pulmonary epithelial cells. After being inhaled, A. fumigatus conidia adhere to and are endocytosed by the epithelial cells that line the alveoli. In susceptible hosts, these conidia then germinate to form hyphae, which exit the pulmonary epithelial cells and invade the deeper tissues. During the previous project period, we identified key transcriptional regulators of A. fumigatus that govern both its interactions with host cells in vitro and virulence during invasive disease in immunosuppressed mice. Using transcriptional profiling, we uncovered potential target genes of these transcriptional regulators. Our preliminary data indicate that these target genes encode newly identified virulence factors that are important for the pathogenic interactions of A. fumigatus with pulmonary epithelial cells and the innate immune system. The experiments described in this proposal will identify and characterize two types of newly discovered A. fumigatus surface molecules and their host cell receptors. The first is A. fumigatus galactosaminogalactan (GAG), which is a novel pathogen-associated molecular pattern (PAMP) that likely plays important roles in both adherence to host constituents and modulation of the inflammatory response. The second set of fungal cell surface molecules consists of three A. fumigatus proteins that likely function as fungal ligands which mediate the pathogenic interactions of this organism with pulmonary epithelial cells. We will investigate both types of surface molecules by: (1) determining the roles of GAG and the candidate fungal ligands in host cell interactions in vitro;(2) elucidating the mechanisms by which they influence virulence in mouse models of invasive pulmonary aspergillosis;and (3) identifying their cognate host cell receptors. Furthermore, we will determine if and how GAG influences the function and surface expression of the fungal ligands, and whether the fungal ligands in turn influence the surface exposure of GAG and ?-glucan. Utilizing this body of research, our ultimate goal is to develop new therapeutic strategies to block A. fumigatus adherence and invasion. It is imperative to improve therapy for invasive aspergillosis because of the expanding population of immunocompromised patients who at high risk for this serious and life-threatening disease.
Aspergillus fumigatus is the principal cause of invasive aspergillosis, which is a frequently deadly and increasingly common disease in immunocompromised patients. The goal of this project is to identify new A. fumigatus virulence factors and their host cell targets in order to develop new approaches to diagnose, prevent, and treat this serious disease.
|Lee, Mark J; Geller, Alexander M; Bamford, Natalie C et al. (2016) Deacetylation of Fungal Exopolysaccharide Mediates Adhesion and Biofilm Formation. MBio 7:e00252-16|
|Lee, Mark J; Sheppard, Donald C (2016) Recent advances in the understanding of the Aspergillus fumigatus cell wall. J Microbiol 54:232-42|
|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|
|Sheppard, Donald C; Filler, Scott G (2014) Host cell invasion by medically important fungi. Cold Spring Harb Perspect Med 5:a019687|
|Lee, Mark J; Gravelat, Fabrice N; Cerone, Robert P et al. (2014) Overlapping and distinct roles of Aspergillus fumigatus UDP-glucose 4-epimerases in galactose metabolism and the synthesis of galactose-containing cell wall polysaccharides. J Biol Chem 289:1243-56|
|Gebremariam, Teclegiorgis; Liu, Mingfu; Luo, Guanpingsheng et al. (2014) CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest 124:237-50|
|Bertuzzi, Margherita; Schrettl, Markus; Alcazar-Fuoli, Laura et al. (2014) The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathog 10:e1004413|
|Luo, Guanpingsheng; Gebremariam, Teclegiorgis; Lee, Hongkyu et al. (2013) Efficacy of liposomal amphotericin B and posaconazole in intratracheal models of murine mucormycosis. Antimicrob Agents Chemother 57:3340-7|
|Filler, Scott G (2013) Can host receptors for fungi be targeted for treatment of fungal infections? Trends Microbiol 21:389-96|
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