Date Published: August 22, 2013
Publisher: Public Library of Science
Author(s): Fabrice N. Gravelat, Anne Beauvais, Hong Liu, Mark J. Lee, Brendan D. Snarr, Dan Chen, Wenjie Xu, Ilia Kravtsov, Christopher M. Q. Hoareau, Ghyslaine Vanier, Mirjam Urb, Paolo Campoli, Qusai Al Abdallah, Melanie Lehoux, Josée C. Chabot, Marie-Claude Ouimet, Stefanie D. Baptista, Jörg H. Fritz, William C. Nierman, Jean Paul Latgé, Aaron P. Mitchell, Scott G. Filler, Thierry Fontaine, Donald C. Sheppard, Tamara L. Doering.
Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall β-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis.
The incidence of invasive mold infections due to the fungus Aspergillus fumigatus has increased dramatically in hematology patients receiving intensive cytotoxic chemotherapy or undergoing hematopoietic stem cell transplantation . Despite the advent of new antifungal therapies, the mortality of invasive aspergillosis (IA) remains 60–80% . There is therefore a pressing need for novel therapeutic strategies to treat or prevent IA. A better understanding of the pathogenesis of IA is one approach that may inform the development of new therapeutic targets.
In A. fumigatus, GAG is a heterogeneous linear polymer consisting of α1–4 linked galactose and N-acetylgalactosamine residues in variable combination . GAG is secreted and also a component of both the amorphous cell wall and extracellular matrix. In addition, GAG has been detected in lung lesions of experimentally infected animals . The present study adds significantly to our understanding of the biosynthesis and function of this fungal polysaccharide.