Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction.
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.
Netea
Mihai G
MG
Department of Medicine (541), University Medical Center St. Radboud, 6500 HB Nijmegen, The Netherlands.
Warris
Adilia
A
Van der Meer
Jos W M
JW
Fenton
Matthew J
MJ
Verver-Janssen
Trees J G
TJ
Jacobs
Liesbeth E H
LE
Andresen
Tonje
T
Verweij
Paul E
PE
Kullberg
Bart Jan
BJ
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
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