Netea Mihai G, Warris Adilia, Van der Meer Jos W M, Fenton Matthew J, Verver-Janssen Trees J G, Jacobs Liesbeth E H, Andresen Tonje, Verweij Paul E, Kullberg Bart Jan
Department of Medicine (541), University Medical Center St. Radboud, 6500 HB Nijmegen, The Netherlands.
J Infect Dis. 2003 Jul 15;188(2):320-6. doi: 10.1086/376456. Epub 2003 Jul 1.
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.
当用烟曲霉的分生孢子而非菌丝刺激时，来自Toll样受体（TLR）4缺陷型ScCr小鼠的腹膜巨噬细胞产生的肿瘤坏死因子、白细胞介素（IL）-1α和IL-1β比对照小鼠的巨噬细胞少，这一发现表明TLR4介导的信号在萌发过程中丧失。使用对烟曲霉的分生孢子有反应但对其菌丝无反应的TLR4特异性成纤维细胞报告细胞系（3E10）证实了这一假设。相比之下，来自TLR2基因敲除小鼠的巨噬细胞对烟曲霉分生孢子和烟曲霉菌丝的反应中促炎细胞因子的产生均减少，并且这些结果在用人类TLR2转染的3E10细胞中得到证实。此外，烟曲霉菌丝而非烟曲霉分生孢子通过依赖TLR2的机制刺激IL-10的产生。总之，TLR4介导的促炎信号在烟曲霉萌发为菌丝时丧失，但TLR2诱导的抗炎信号并未丧失。因此，萌发过程中的表型转换可能是烟曲霉的一种重要逃逸机制，可导致对抗宿主防御。
