Aspergillus Galactosaminogalactan Mediates Adherence to Host Constituents and Conceals Hyphal β-Glucan from the Immune System

Fabrice N Gravelat,Brendan D Snarr,Aaron P Mitchell,Dan Chen,Stefanie D Baptista,Thierry Fontaine,William C Nierman,Jörg H Fritz,Anne Beauvais,Ilia Kravtsov,Wenjie Xu,Mark J Lee,Ghyslaine Vanier,Donald C Sheppard,Paolo Campoli,Qusai Al Abdallah,Hong Liu,Mirjam Urb,Jean Paul Latgé,Scott G Filler,Josée C Chabot,Mélanie Lehoux ,Christopher M.-Q Hoareau ,Marie Claude Ouimet

doi:10.1371/journal.ppat.1003575

Abstract

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.

Highlights

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 [1]
Since Nacetyl galactosamine is a key component of galactosaminogalactan (GAG), a glycan found within the amorphous cell wall and extracellular matrix of A. fumigatus during infection [15,16], these results suggested that GAG is involved in the differential adhesive properties of these mutants
A trend to lower levels of the anti-inflammatory cytokine IL-10 produced by bone marrow derived dendritic cells (BMDDCs) infected with the Duge3 mutant as compared with hyphae of wild-type A. fumigatus was observed, this difference was not statistically significant. To confirm these results and determine if this increased proinflammatory response induced by the Duge3 mutant was mediated by increased binding to dectin-1, we examined the ability of an anti-dectin-1 neutralizing antibody and Fc-dectin-1 to block the increase in TNF-a production by BMDDCs in response to hyphae of the Duge3 mutant strain

Summary

Introduction

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 [1]. Despite the advent of new antifungal therapies, the mortality of invasive aspergillosis (IA) remains 60–80% [2]. Filamentous hyphae remain in intimate contact with host epithelial, endothelial and immune cells and can induce tissue injury and inflammatory responses. Inhibition of these adherence events may provide a useful therapeutic strategy to reduce morbidity and mortality of A. fumigatus mediated disease

Methods

Results

Conclusion