Abstract
In this study, we analyze the importance of O-linked oligosaccharides present in peptidorhamnomannan (PRM) from the cell wall of the fungus Scedosporium prolificans for recognition and phagocytosis of conidia by macrophages. Adding PRM led to a dose-dependent inhibition of conidia phagocytosis, whereas de-O-glycosylated PRM did not show any effect. PRM induced the release of macrophage-derived antimicrobial compounds. However, O-linked oligosaccharides do not appear to be required for such induction. The effect of PRM on conidia-induced macrophage killing was examined using latex beads coated with PRM or de-O-glycosylated PRM. A decrease in macrophage viability similar to that caused by conidia was detected. However, macrophage killing was unaffected when beads coated with de-O-glycosylated PRM were used, indicating the toxic effect of O-linked oligosaccharides on macrophages. In addition, PRM triggered TNF-α release by macrophages. Chemical removal of O-linked oligosaccharides from PRM abolished cytokine induction, suggesting that the O-linked oligosaccharidic chains are important moieties involved in inflammatory responses through the induction of TNF-α secretion. In summary, we show that O-glycosylation plays a role in the recognition and uptake of S. prolificans by macrophages, killing of macrophages and production of pro- inflammatory cytokines.
Highlights
Scedosporium prolificans is an opportunistic pathogen, responsible for serious infections in immunocompetent as well as immunocompromised patients, due to its high virulence and antifungal multidrug resistance [1, 2].Cell wall surface glycoconjugates from the Scedosporium/Pseudallescheria boydii complex are thought to be the first point of contact between the fungus and cells of the innate immune system [3, 4]
Peptidorhamnomannans (PRMs) are common cell wall components that are found in P. boydii [7], S. apiospermum [13] and S. prolificans [11]
O-linked oligosaccharides ranging from tri- to hexasaccharides were isolated from PRM of P. boydii mycelia and of S. prolificans mycelia and conidia [5, 11, 13] and their immunodominance was evaluated [5, 7, 18]
Summary
Scedosporium prolificans is an opportunistic pathogen, responsible for serious infections in immunocompetent as well as immunocompromised patients, due to its high virulence and antifungal multidrug resistance [1, 2].Cell wall surface glycoconjugates from the Scedosporium/Pseudallescheria boydii complex are thought to be the first point of contact between the fungus and cells of the innate immune system [3, 4]. N- and O-linked peptidorhamnomannans are major pathogen-associated molecular patterns and along with α-glucans, play important roles in triggering host innate immunity [3, 5, 6]. Rhamnose-containing structures appear to be immunodominant epitopes in the peptidorhamnomannans isolated from mycelia of P. boydii, S. prolificans and S. apiospermum, if they are present as (1!3)-linked α-Rhap side chain units [7,8,9,10]. Antibodies recognizing this structure may, recognize both the N-linked high molecular weight polysaccharides and the O-linked oligosaccharides in the glycocomplexes. We analyzed how the glycosylation of S. prolificans proteins influences the recognition and uptake of S. prolificans by macrophages, as well as its role in killing macrophages and promoting the production of proinflammatory cytokines
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