title: Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction.
abstract: Peritoneal macrophages from Toll-like receptor (TLR) 4-deficient ScCr mice produced less tumor necrosis factor, interleukin (IL)-1alpha, and IL-1beta than did macrophages of control mice, when stimulated with conidia, but not with hyphae, of Aspergillus fumigatus, a finding suggesting that TLR4-mediated signals are lost during germination. This hypothesis was confirmed by use of a TLR4-specific fibroblast reporter cell line (3E10) that responded to the conidia, but not to the hyphae, of A. fumigatus. In contrast, macrophages from TLR2-knockout mice had a decreased production of proinflammatory cytokines in response to both Aspergillus conidia and Aspergillus hyphae, and these results were confirmed in 3E10 cells transfected with human TLR2. In addition, Aspergillus hyphae, but not Aspergillus conidia, stimulated production of IL-10 through TLR2-dependent mechanisms. In conclusion, TLR4-mediated proinflammatory signals, but not TLR2-induced anti-inflammatory signals, are lost on Aspergillus germination to hyphae. Therefore, phenotypic switching during germination may be an important escape mechanism of A. fumigatus that results in counteracting the host defense.
authors.affiliation: Department of Medicine (541), University Medical Center St. Radboud, 6500 HB Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
authors.forename: Jos W M
authors.initials: JW
authors.lastname: Van der Meer
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fenton
authors.forename: Trees J G
authors.initials: TJ
authors.lastname: Verver-Janssen
authors.forename: Liesbeth E H
authors.initials: LE
authors.lastname: Jacobs
authors.forename: Tonje
authors.initials: T
authors.lastname: Andresen
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D025301:Hyphae / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10