Wild-type measles virus infection in human CD46/CD150-transgenic mice: CD11c-positive dendritic cells establish systemic viral infection
Wild-type measles virus infection in human CD46/CD150-transgenic mice: CD11c-positive dendritic cells establish systemic viral infection
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DOI：
10.4049/jimmunol.175.5.3252
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Seya, T
中科院分区：
文献类型：
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作者：
Shingai, M;Inoue, N;Seya, T
我们产生了组成型表达人CD 46（huCD 46）和/或TLR诱导型CD 150（huCD 150）的转基因（TG）小鼠，这些小鼠可作为麻疹病毒（MV）的受体。这些小鼠用于研究表达GFP或完整的实验室适应的Edmonston和野生型Ichinose（IC）MV菌株的传播和致病性。无论给药途径如何，两种类型的MV对这些TG小鼠均无致病性。然而，在离体中，在来自huCD 46/buCD 150 TG和huCD 150 TG的脾淋巴细胞中观察到IC的有限复制，但在huCD 46 TG和非TG小鼠中未观察到IC的复制。在huCD 150阳性TG小鼠细胞中，CD 11 c阳性骨髓来源的髓样树突状细胞（mDC）参与MV介导的I型IFN诱导。在mDC中IFN-β的水平和诱导概况高于IFN-α的概况。与Edmonston相比，野生型IC在mDC中诱导显著高水平的IFN-β，而不是人树突状细胞。然后我们用I型IFN受体（IFNAR 1）-/-小鼠产生huCD 46/huCD 150 TG小鼠。通过腹膜内注射MV，在这些三重突变小鼠体内清楚地观察到携带MV的mDC扩散到引流淋巴结。在静脉内转移MV感染的CD 11 c阳性mDC的双TG小鼠中也检测到感染性淋巴结。这一发现表明，在双TG小鼠模型中，mDC一旦感染就促进全身MV传播和感染，这取决于由经由IFNAR 1产生的I型IFN的水平确定的mDC MV容许性。尽管这些结果可能并不能简单地反映人类MV感染，但huCD 150/huCD 46 TG小鼠可以作为分析MV依赖性调节mDC反应的有用模型。
We generated transgenic (TG) mice that constitutively express human CD46 (huCD46) and/or TLR-inducible CD150 (huCD150), which serve as receptors for measles virus (MV). These mice were used to study the spreading and pathogenicity of GFPexpressing or intact laboratory-adapted Edmonston and wild-type Ichinose (IC) strains of MV. Irrespective of the route of administration, neither type of MV was pathogenic to these TG mice. However, in ex vivo, limited replication of IC was observed in the spleen lymphocytes from huCD46/buCD150 TG and huCD150 TG, but not in huCD46 TG and non-TG mice. In huCD150-positive TG mouse cells, CD11c-positive bone marrow-derived myeloid dendritic cells (mDC) participated in MV-mediated type I IFN induction. The level and induction profile of IFN-beta was higher in mDC than the profile of IFN-alpha. Wild-type IC induced markedly high levels of IFN-beta compared with Edmonston in mDC, as opposed to human dendritic cells. We then generated huCD46/huCD150 TG mice with type I IFN receptor (IFNAR1)-/- mice. MV-bearing mDCs spreading to draining lymph nodes were clearly observed in these triple mutant mice in vivo by i.p. MV injection. Infectious lymph nodes were also detected in the double TG mice into which MV-infected CD11c-positive mDCs were i.v. transferred. This finding suggests that in the double TG mouse model mDCs once infected facilitate systemic MV spreading and infection, which depend on mDC MV permissiveness determined by the level of type I IFN generated via IFNAR1. Although these results may not simply reflect human MV infection, the huCD150/huCD46 TG mice may serve as a useful model for the analysis of MV-dependent modulation of mDC response.