The Fungal Exopolysaccharide Galactosaminogalactan Mediates Virulence by Enhancing Resistance to Neutrophil Extracellular Traps

• DOI: 10.1371/journal.ppat.1005187
• Publication Date: 2015-10-22T17:56:40Z
• Authors: Mark J. Lee; Hong Liu; Bridget M. Barker; Brendan D. Snarr; Fabrice N. Gravelat; Qusai Al Abdallah; Christina Gavino; Shane R. Baistrocchi; Hanna Ostapska; Tianli Xiao; Benjamin Ralph; Norma V. Solis; Mélanie Lehoux; Stefanie D. Baptista; Arsa Thammahong; Robert P. Cerone; Susan G. W. Kamin...; Marie-Christine G...; Jean-Paul Latgé; Thierry Fontaine; Donald C. Vinh; Scott G. Filler; Donald C. Sheppard
• Keywords: Neutrophils; MESH: Neutrophils; MESH: Virulence; Inbred C57BL; Extracellular Traps; Mice; 2.2 Factors relating to the physical environment; MESH: Animals; Aetiology; Biology (General); Inbred BALB C; [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology; Mice, Inbred BALB C; 0303 health sciences; Virulence factors; Virulence; Biological Sciences; Medical microbiology; 3. Good health; Infectious Diseases; Aspergillus; Medical Microbiology; MESH: Aspergillus; Infection; Cell walls; Research Article; 570; QH301-705.5; Clinical Sciences; Immunology; MESH: Mice, Inbred BALB C; 610; MESH: Biofilms; Microbiology; Aspergillus nidulans; 03 medical and health sciences; Rare Diseases; MESH: Mice, Inbred C57BL; Polysaccharides; Virology; Genetics; Animals; Fungal diseases; MESH: Mice; Biomedical and Clinical Sciences; Invasive species; Aspergillus fumigatus; MESH: Extracellular Traps; RC581-607; Mice, Inbred C57BL; Emerging Infectious Diseases; MESH: Polysaccharides; Biofilms; Immunologic diseases. Allergy

Of the over 250 Aspergillus species, Aspergillus fumigatus accounts for up to 80% of invasive human infections. A. fumigatus produces galactosaminogalactan (GAG), an exopolysaccharide composed of galactose and N-acetyl-galactosamine (GalNAc) that mediates adherence and is required for full virulence. Less pathogenic Aspergillus species were found to produce GAG with a lower GalNAc content than A. fumigatus and expressed minimal amounts of cell wall-bound GAG. Increasing the GalNAc content of GAG of the minimally pathogenic A. nidulans, either through overexpression of the A. nidulans epimerase UgeB or by heterologous expression of the A. fumigatus epimerase Uge3 increased the amount of cell wall bound GAG, augmented adherence in vitro and enhanced virulence in corticosteroid-treated mice to levels similar to A. fumigatus. The enhanced virulence of the overexpression strain of A. nidulans was associated with increased resistance to NADPH oxidase-dependent neutrophil extracellular traps (NETs) in vitro, and was not observed in neutropenic mice or mice deficient in NADPH-oxidase that are unable to form NETs. Collectively, these data suggest that cell wall-bound GAG enhances virulence through mediating resistance to NETs.