MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans
MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans
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DOI：
10.1002/eji.200425799
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发表时间：
2005-03-01
影响因子：
5.4
通讯作者：
Mancuso, G
中科院分区：
文献类型：
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作者：
Biondo, C;Midiri, A;Mancuso, G
我们研究了Toll样受体（TLR）和衔接蛋白MyD 88在新生隐球菌（一种致病性包囊酵母）先天免疫应答中的潜在作用。与野生型对照组相比，MyD 88（-/-）或TLR 2（-/-）小鼠的腹膜巨噬细胞在体外用全酵母刺激后释放的TNF-α显著减少。相比之下，相对于C3 H/HeN对照，在来自C3 H/HeJ小鼠的巨噬细胞之间没有注意到TNF-α释放的差异，所述C3 H/HeJ小鼠在TLR 4中具有功能缺失突变。当MyD 88或TLR 2缺陷小鼠感染低剂量的H99血清型A菌株时，所有对照动物，但MyD 88（-/-）动物无一存活，仅38%的TLR 2（-/-）动物存活，这与突变小鼠中较高的真菌负荷有关。MyD 88（-/-）和TLR 2（-/-）动物在感染期间在各种器官中均显示TNF-α、IL-12 p40和/或IFN-γ表达降低。C3 H/HeJ小鼠和C3 H/HeN对照小鼠对实验性隐球菌病的易感性无差异。总之，我们的数据表明，TLR 2和MyD 88，而不是TLR 4，通过诱导增加TNF-α，IL-12和IFN-γ的表达，对抗隐球菌防御起关键作用。
We investigated here the potential role of Toll-like receptors (TLR) and the adaptor protein MyD88 in innate immunity responses to Cryptococcus neoformans, a pathogenic encapsulated yeast. Peritoneal macrophages from MyD88(-/-) or TLR2(-/-) mice released significantly less TNF-alpha, compared with wild-type controls, after in vitro stimulation with whole yeasts. In contrast, no differences in TNF-alpha release were noted between macrophages from C3H/HeJ mice, which have a loss of function mutation in TLR4, relative to C3H/HeN controls. When MyD88- or TLR2-deficient mice were infected with low doses of the H99 serotype A strain, all of the control animals, but none of MyD88(-/-) and only 38% of the TLR2(-/-) animals survived, in association with higher fungal burden in the mutant mice. Both MyD88(-/-) and TLR2(-/-) animals showed decreased TNF-alpha, IL-12p40 and/or IFN-gamma expression in various organs during infection. No difference in susceptibility to experimental cryptococcosis was found between C3H/HeJ mice and C3H/HeN controls. In conclusion, our data indicate that TLR2 and MyD88, but not TLR4, critically contribute to anti-cryptococcal defenses through the induction of increased TNF-alpha, IL-12 and IFN-gamma expression.