A Nonredundant Role for Plasmacytoid Dendritic Cells in Host Defense against the Human Fungal Pathogen Aspergillus fumigatus

Abstract

Summary: While plasmacytoid dendritic cells (pDCs), a natural type I interferon (IFN) producing cell type, are regarded as critical for innate immunity to viruses, their role in defense against fungal infections remains unknown. We examined the interactions of pDCs with hyphae of the invasive human fungal pathogen Aspergillus fumigatus. Human pDCs spread over hyphae and inhibited their growth. Antifungal activity was retained in pDC lysates, did not require direct fungal contact, and was partially reversed by zinc. Incubation with hyphae resulted in pDC cytotoxicity, partly due to fungal gliotoxin secretion. Following hyphal stimulation, pDCs released proinflammatory cytokines via a TLR9-independent mechanism. Pulmonary challenge of mice with A. fumigatus resulted in a substantial influx of pDCs into lungs and pDC-depleted mice were hypersusceptible to invasive aspergillosis. These data demonstrate the antifungal activity of pDCs against A. fumigatus and establish their non-redundant role in host defenses against invasive aspergillosis in vivo.

Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection

“…S100A8 and S100A9, which can collectively form a heterodimer called calprotectin (Lagasse & Clerc, 1988;Odink et al, 1987;Zwadlo et al, 1988), are involved in neutrophil recruitment and are known to be produced by epithelial cells following induction by IL-22 (Aujla et al, 2008;Kolls et al, 2008;Liang et al, 2006). S100 proteins are calcium-binding cytosolic proteins that can be expressed by multiple cell types, including alveolar epithelial cells, endothelial cells, monocytes, macrophages, neutrophils and dendritic cells (DCs) (Ehrchen et al, 2009;Foell et al, 2007;Ramirez-Ortiz et al, 2011). Importantly, calprotectin may have direct antifungal and fungistatic activity against fungi, including C. neoformans (Mambula et al, 2000;McCormick et al, 2010;Urban et al, 2009).…”

Antifungal Activity of Plasmacytoid Dendritic Cells against Cryptococcus neoformans In Vitro Requires Expression of Dectin-3 (CLEC4D) and Reactive Oxygen Species

“…This distinction has also been observed with Aspergillus fumigatus. Ramirez-Ortiz et al showed in 2011 that pDCs are capable of inhibiting A. fumigatus hyphal growth, in contrast to neutrophils and monocytes, which are able to kill A. fumigatus (21). The inhibition of A. fumigatus growth by pDCs was shown to be mediated by calprotectin, which was released as a result of pDC death, induced by a gliotoxin produced by the fungus (21).…”

“…However, there is limited information regarding a role for pDCs in mediating the host defense against fungal pathogens. During Aspergillus infections, pDCs are required for protection (21), and mice resistant to Paracoccidioides brasiliensis exhibited higher numbers of pDCs in the lungs 96 h postinfection than mice that succumbed to the infec- 4 CFU of C. neoformans strain H99␥. Prior to and during infection, mice were treated either with an isotype control antibody or with an anti-CXCR3 antibody.…”

“…1C). This is noteworthy in view of the fact that inhibition of the growth of A. fumigatus by pDCs has been shown to be mediated by calprotectin, which was released as a result of pDC death (21), and by the formation of extracellular traps by pDCs (24).…”

“…However, little is known about the role of pDCs in response to fungal infections. Ramirez-Ortiz et al have shown that pDCs are indispensable for protection against Aspergillus fumigatus infections in mice (21). pDCs mediate direct antifungal activity against A. fumigatus hyphae and conidia via the release of calprotectin, and depletion of pDCs in infected mice resulted in a significant decrease in survival from that of control mice with intact pDC numbers (21).…”