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

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

doi:10.1371/journal.ppat.1003575

Cited by 258 publications

(418 citation statements)

References 49 publications

(74 reference statements)

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“…S7). The fungal burden of the Sph3 h -treated mice was similar to that observed with mice infected with the GAG-deficient hypovirulent strain Δuge3 (20). Consistent with the fungal burden data, histopathologic examination of lung sections revealed the presence of fungal lesions in untreated, infected mice, but no detectable lesions in the lungs of infected mice treated with Sph3 h , or those infected with conidia of the Δuge3 mutant (Fig.…”

Section: Intratracheal Sph3 H Is Well Tolerated and Attenuates Fungasupporting

confidence: 82%

“…A549 pulmonary epithelial cell damage by A. fumigatus was tested by using the 51 Cr release assay as described (20,30). Recombinant hydrolases were added to the A549 cultures at the time of infection at a final concentration of 0.5 μM.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were immunosuppressed with cortisone acetate and cyclophosphamide as described (20,41). Mice were infected with an endotracheal injection of 5 × 10 3 A. fumigatus conidia, resuspended in either PBS alone, or in combination with 500 μg of Sph3 h .…”

Section: Methodsmentioning

confidence: 99%

“…A. fumigatus GAG-mediated adherence is required for A. fumigatus to damage A549 pulmonary epithelial cells in vitro (20). We therefore tested whether treatment with either Sph3 h or PelA h could protect epithelial cells from fungalinduced injury by using an established chromium ( 51 Cr) release damage assay (30).…”

Section: Sph3 H and Pela H Potentiate Antifungals By Enhancing Theirmentioning

confidence: 99%

“…Strains of Aspergillus and P. aeruginosa with impaired GAG, or Pel and Psl biosynthesis exhibit attenuated virulence (20,21), suggesting that targeting these exopolysaccharides may be a…”

mentioning

confidence: 99%

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Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Snarr

Baker

Bamford

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa, respectively. These exopolysaccharides both contain 1,4-linked N-acetyl-D-galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3 h from A. fumigatus and PelA h from P. aeruginosa) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3 h disrupted A. fumigatus biofilms with an EC 50 of 0.4 nM. PelA h treatment also disrupted preformed A. fumigatus biofilms with EC 50 values similar to those obtained for Sph3 h . In contrast, Sph3 h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3 h or PelA h significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus-induced cell damage for up to 24 h. Intratracheal administration of Sph3 h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.biofilm | Aspergillus | Pseudomonas | therapeutics | exopolysaccharide

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Section: Intratracheal Sph3 H Is Well Tolerated and Attenuates Fungasupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Sph3 H and Pela H Potentiate Antifungals By Enhancing Theirmentioning

confidence: 99%

“…Strains of Aspergillus and P. aeruginosa with impaired GAG, or Pel and Psl biosynthesis exhibit attenuated virulence (20,21), suggesting that targeting these exopolysaccharides may be a…”

mentioning

confidence: 99%

See 3 more Smart Citations

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Snarr

Baker

Bamford

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

et al. 2020

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Aspergillosis is a life-threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host-pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement-dependent effector with protective functions against A. fumigatus.Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.Aspergillus fumigatus is an evolutionary ancient filamentous fungus (mold) that flourishes in soil and decomposing vegetation [1]. Traditionally regarded as asexual, the life cycle of this ubiquitous saprophyte actually comprises cryptic forms of sexual reproduction [2] and is hallmarked by several morphotypes with distinct metabolic, compositional, and structural traits [3]. The metabolically inactive and asexual airborne spores (known as dormant or resting conidia) are encased in a robust cell wall mostly made of complex polysaccharides [i.e., aand b-glucans, chitin, galactomannan (GM), and galactosaminogalactan (GAG)] in addition to lipids, proteins, and melanin pigments [i.e., dihydroxynaphthalene (DHN) melanin] [4]. Small in size (i.e., 2-3 µm across) and enveloped in a layer of hydrophobic rodlet-like proteins (i.e.

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Synthesis and Structural Analysis of Aspergillus fumigatus Galactosaminogalactans Featuring α‐Galactose, α‐Galactosamine and α‐N‐Acetyl Galactosamine Linkages

et al. 2020

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Galactosaminogalactan (GAG) is a prominent cell wall component of the opportunistic fungal pathogen Aspergillus fumigatus. GAG is a heteropolysaccharide composed of α‐1,4‐linked galactose, galactosamine and N‐acetylgalactosamine residues. To enable biochemical studies, a library of GAG‐fragments was constructed featuring specimens containing α‐galactose‐, α‐galactosamine and α‐N‐acetyl galactosamine linkages. Key features of the synthetic strategy include the use of di‐tert‐butylsilylidene directed α‐galactosylation methodology and regioselective benzoylation reactions using benzoyl‐hydroxybenzotriazole (Bz‐OBt). Structural analysis of the Gal, GalN and GalNAc oligomers by a combination of NMR and MD approaches revealed that the oligomers adopt an elongated, almost straight, structure, stabilized by inter‐residue H‐bonds, one of which is a non‐conventional C−H⋅⋅⋅O hydrogen bond between H5 of the residue (i+1) and O3 of the residue (i). The structures position the C‐2 substituents almost perpendicular to the oligosaccharide main chain axis, pointing to the bulk solvent and available for interactions with antibodies or other binding partners.

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

Cited by 258 publications

References 49 publications

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

Synthesis and Structural Analysis of Aspergillus fumigatus Galactosaminogalactans Featuring α‐Galactose, α‐Galactosamine and α‐N‐Acetyl Galactosamine Linkages

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