Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

Abstract

Aspergillus species are saprophytic molds causing life-threatening invasive fungal infections in the immunocompromised host. Innate immune recognition, in particular, the mechanisms of opsonization and complement activation, has been reported to be an integral part of the defense against fungi. We have shown that the complement component ficolin-A significantly binds to Aspergillus conidia and hyphae in a concentration-dependent manner and was inhibited by N-acetylglucosamine and N-acetylgalactosamine. Calcium-independent binding to Aspergillus fumigatus and A. terreus was observed, but binding to A. flavus and A. niger was calcium dependent. Ficolin-A binding to conidia was increased under low-pH conditions, and opsonization led to enhanced binding of conidia to A549 airway epithelial cells. In investigations of the lectin pathway of complement activation, ficolin-A-opsonized conidia did not lead to lectin pathway-specific C4 deposition. In contrast, the collectin mannose binding lectin C (MBL-C) but not MBL-A led to efficient lectin pathway activation on A. fumigatus in the absence of ficolin-A. In addition, ficolin-A opsonization led to a modulation of the proinflammatory cytokine interleukin-8. We conclude that ficolin-A may play an important role in the innate defense against Aspergillus by opsonizing conidia, immobilizing this fungus through enhanced adherence to epithelial cells and modulation of inflammation. However, it appears that other immune pattern recognition molecules, i.e., those of the collectin MBL-C, are involved in the Aspergillus-lectin complement pathway activation rather than ficolin-A.

Ficolins Promote Fungal Clearance in vivo and Modulate the Inflammatory Cytokine Response in Host Defense against <b><i>Aspergillus fumigatus</i></b>

“…Specifically, it was shown that ficolin-2 stimulated murine macrophages to produce IFN-γ, IL-17A, TNF-α and IL-6 in vitro, and that ficolin-A KO mice exhibited decreased production of TNF-α and IL-17A in vivo upon stimulation with LPS [26]. Other investigators reported that ficolin-A increased the production of IL-8 from human lung epithelial cells following A. fumigatus challenge in vitro [29] . On the other hand, the same group showed that ficolin-A or ficolin-2 opsonization of A. fumigatus leads to decreased levels of IL-8, IL-1β, IL-6, and TNF-α from human monocyte-derived macrophages and neutrophils [30,34].…”

“…1a). Recent studies showed that ficolin-A opsonization of A. fumigatus conidia enhanced the binding of conidia to A549 airway epithelial cells [29], human monocyte-derived macrophages and neutrophils [30]. Consequently, hyphal growth was inhibited and fungal killing was increased.…”

“…These results are consistent with another study where the contribution of ficolins to complement activation on A. fumigatus was investigated . The investigators used WT, ficolin-A- or MBL-deficient mouse sera and reported that ficolin-A-bound A. fumigatus conidia did not activate the lectin complement pathway, but that complement deposition was mediated via binding of MBL-C [29]. In addition, PTX3 has been shown to activate complement on A. fumigatus [39].…”

“…In addition, in vivo studies have demonstrated a protective effect of ficolins in murine models of bacterial and viral infections [20,24,25,26]. While in vitro studies suggest that ficolins participate in the elimination of A. fumigatus [27,28,29,30,31], the in vivo role of ficolins during fungal infection has not yet been addressed. Therefore, we used ficolin-deficient mice to elucidate the role of ficolins in host defense against A. fumigatus infection in the present study.…”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…Three different ficolins exist in humans, ficolin-1 (FCN-1/M-ficolin), ficolin-2 (FCN-2/L-ficolin), and ficolin-3 (FCN-3/H-ficolin), while mice only possess an ortholog of human FCN-2, termed ficolin-A. Initial studies demonstrated that although ficolin-A opsonized A. fumigatus and had enhanced binding to human lung epithelial cells, ficolin-Aopsonized conidia did not lead to lectin pathway-specific C4 deposition [41] . Ficolin-A opsonized A. fumigatus did, however, augment human lung epithelial cell IL-8 production.…”