Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

Abstract

Aspergillus fumigatus is a common cause of invasive and allergic pulmonary disease. Resting conidia of the filamentous fungus are constantly inhaled, but cause infection only after initiating hyphal growth. In this study, we have explored whether macrophages can distinguish between resting spores and the maturing, potentially invasive form of the fungus. Although macrophages bind and ingest A. fumigatus resting conidia efficiently, there is little inflammatory response; NF-κβ is not activated, inflammatory cytokines are not induced, and reactive oxygen species are not produced. However, maturing A. fumigatus conidia and germ tubes stimulate NF-κβ, secretion of proinflammatory cytokines and production of reactive oxygen by human monocyte-derived macrophages and murine macrophages from multiple anatomical sites. These responses are in part mediated by dectin-1, which binds cell wall β-glucan that is not present on the surface of dormant conidia, but is present after cellular swelling and loss of the hydrophobic proteinaceous cell wall. Dectin-1 binding to germ tubes augments, but is not required for, TLR2-mediated inflammatory cytokine secretion. Dectin-1 recognition of germ tubes also stimulates TNF-α production in the absence of both TLR2 and MyD88 signaling. These data demonstrate one mechanism by which the pulmonary inflammatory response is tailored toward metabolically active cells, thereby avoiding unnecessary tissue damage with frequent inhalation of ubiquitous spores.

Phagocytic Effects of β-Glucans from the Mushroom Coriolus versicolor are Related to Dectin-1, NOS, TNF-α Signaling in Macrophages

“…This concept is supported by a report that ROS production by β-glucans was partially inhibited by laminarin, which could indicate the involvement of other receptors (Gersuk et al, 2006). However, recent evidence also showed that SCG and NaClO-oxidized zymosan (which contained only β-glucan)-induced production of TNF-α, IL-12, and IFN-γ, via dectin-1 signaling, was not affected by a defi ciency in MyD88, indicating its effect was independent of the TLR pathway (Saijo et al, 2007).…”

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…Dectin-1 is the most important receptor described to interact with b-glucans of different types of fungi [9,17,[20][21][22]. Whereas neutrophils and macrophages show heterogeneous but strong expression of dectin-1 [16,38], dectin-1 expression on DC subsets is not well defined.…”

“…Blocking experiments showed that the uptake was dependent on the recognition of b-glucans by dectin-1 for both DC subsets, suggesting that the low dectin-1 expression was functional. b-Glucans are conserved cell wall components of fungi and dectin-1 has been shown to recognize many pathogenic fungi like C. albicans, P. carinii and A. fumigatus [9,17,[20][21][22]. Therefore, dectin-1 expression on mouse DC would enable them to induce adaptive immune responses against these pathogens, although this has not extensively been investigated in vivo [23,24].…”

“…b-Glucans are hidden in a layer of mannosylated proteins and chitin, but they can be exposed on the surface of fungi in budscars and following heatinactivation of the yeasts [19]. Dectin-1 recognizes zymosan and Saccharomyces cerevisiae, but also pathogenic fungi like C. albicans, Pneumocystis carinii and A. fumigatus [9,17,[20][21][22]. Recent studies with dectin-1-deficient mice show the importance of dectin-1 for the immune response towards fungal infections in vivo [23,24].…”

Histoplasma capsulatumα-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor

“…Consistent with this hypothesis, the parasitic forms of the dimorphic fungal pathogens each possess ␣-(1,3)-glucan and can cause disease even in the face of normal host immune function. The fungal pathogen Aspergillus fumigatus also appears to limit ␤-glucan exposure by as yet unknown mechanisms because no ␤-glucan is detected on resting conidia until the conidia germinate (20)(21)(22). The opportunistic fungal pathogen C. albicans lacks ␣-(1,3)-glucan and does not typically cause disease in healthy hosts.…”