Modulation of Toll-Like Receptor 2 (TLR2) and TLR4 Responses byAspergillus fumigatus

Abstract

Toll-like receptor (TLR)-based signaling pathways in the host may be modulated by pathogens during the course of infection. We describe a novel immunomodulatory mechanism in which Aspergillus fumigatus conidia induce attenuation of TLR2-and TLR4-mediated interleukin (IL)-6 and IL-1␤ proinflammatory responses in human mononuclear cells with suppression of IL-1␤ mRNA transcription. Background TLR2 and TLR4 mRNA transcription was not influenced. A. fumigatus conidia induced TLR2 internalization and uptake into the phagosome with a resultant decrease in surface receptor expression. A. fumigatus hyphae, on the other hand, selectively downregulated the TLR4-mediated response. These novel immunosuppressive effects may facilitate the invasiveness of A. fumigatus.Opportunistic fungal infections remain a significant cause of mortality and morbidity in immunocompromised patients. Aspergillus fumigatus is one of the most common infective molds worldwide (7). Acquisition of invasive aspergillosis results from inhalation of airborne conidia, which, in the absence of competent immune containment, is followed by germination, development of hyphae, and invasive disease.Mononuclear phagocytes constitute an important component of host defense against A. fumigatus and also are the precursors of tissue macrophages involved in immune surveillance against invasive pulmonary aspergillosis (29, 31). Their ability to detect specific pathogen-associated molecular patterns of Aspergillus conidia involves expression of pathogen recognition receptors (PRRs), and the main families of these receptors are the Toll-like receptors (TLRs) and the lectin receptors. TLR2 and TLR4 have been reported to mediate recognition of various cell wall components of Aspergillus (2,18,19,40), and dectin-1, a C-type lectin receptor, is the major PRR involved in the recognition of ␤-glucans (21, 29, 32). Although infection experiments with TLR-deficient mice have provided evidence for involvement of TLR2 and TLR4 in the host defense against A. fumigatus (1, 2), the relative importance of both these receptors and other TLRs remains to be determined. In addition, the inflammatory response triggered through TLR2 and TLR4 strongly depends on the Aspergillus morphotype. For example, while conidium recognition was mediated by both TLR2 and TLR4, TLR4-mediated signaling was lost in recognition of hyphae (24). This inability to recognize and fight the most dangerous morphotype could represent an immune evasion mechanism (23). On the other hand, very little is known about whether fungal pathogens can also modulate a TLR-mediated host defense by decreasing the capacity of host cells to respond to TLR2 and TLR4 ligands.The aim of the present study was to study the capacity of A. fumigatus to modulate the host immune response triggered by TLRs. The effects of Aspergillus modulation of TLR2 and TLR4 activation were specifically examined, given that these receptors mediate the major pathways implicated in antifungal host defense. MATERIALS AND METHODSReagents. The TLR2 ligand ...

Toll-Like Receptor 4 Signaling Leads to Severe Fungal Infection Associated with Enhanced Proinflammatory Immunity and Impaired Expansion of Regulatory T Cells

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