Both TRIF and IPS-1 Adaptor Proteins Contribute to the Cerebral Innate Immune Response against Herpes Simplex Virus 1 Infection
Both TRIF and IPS-1 Adaptor Proteins Contribute to the Cerebral Innate Immune Response against Herpes Simplex Virus 1 Infection
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DOI：
10.1128/jvi.00591-13
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发表时间：
2013-07-01
影响因子：
5.4
通讯作者：
Boivin, Guy
中科院分区：
文献类型：
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作者：
Menasria, Rafik;Boivin, Nicolas;Boivin, Guy
Toll样受体（TLR）和RNA解旋酶（RLH）是通过产生I型干扰素（IFN）参与病毒感染的免疫控制的重要细胞传感器。在单纯疱疹病毒1型（HSV-1）脑炎期间，研究了TRIF和IPS-1衔接蛋白（分别涉及TLR 3和RLH信号通路）缺陷的影响。TRIF、-/- IPS-1（-/-）和C57 BL/6野生型（WT）小鼠鼻内感染7.5 × 10（5）PFU HSV-1。在20天内监测小鼠的神经体征和存活率。在感染后第3、5、7、9和11天处死各组小鼠，以通过定量PCR（qPCR）、空斑测定和免疫组织化学测定脑病毒复制，并测定α/β干扰素干扰素调节因子3和7的（IFN-α/β）水平和磷酸化分别通过酶联免疫吸附试验（ELISA）和蛋白质印迹法测定脑匀浆中的IRF-3和IRF-7。TRIF-/-和IPS-1（-/-）小鼠的死亡率高于WT小鼠（分别为P = 0.02和P = 0.09）。病毒抗原在整个脑中的传播更多，与WT的结果相比，TRIF-/-（第5至9天）和IPS-1（-/-）（第7和9天）小鼠的脑病毒载量显著增加相关。与WT的结果相比，在第5天TRIF-/-和IPS-1（-/-）小鼠的脑匀浆中IFN-β产生减少，而在第7天TRIF-/-小鼠中IFN-α水平增加。在TRIF-/-和IPS-1（-/-）小鼠中，IRF-3和IRF-7的磷酸化水平分别降低。这些数据表明，TRIF和IPS-1信号通路对于控制HSV在脑中的复制和通过IFN-β产生的存活都是重要的。
Toll-like receptors (TLRs) and RNA helicases (RLHs) are important cell sensors involved in the immunological control of viral infections through production of type I interferon (IFN). The impact of a deficiency in the TRIF and IPS-1 adaptor proteins, respectively, implicated in TLR3 and RLH signaling pathways, was investigated during herpes simplex virus 1 (HSV-1) encephalitis. TRIF,-/- IPS-1(-/-), and C57BL/6 wild-type (WT) mice were infected intranasally with 7.5 x 10(5) PFU of HSV-1. Mice were monitored for neurological signs and survival over 20 days. Groups of mice were sacrificed on days 3, 5, 7, 9, and 11 postinfection for determination of brain viral replication by quantitative PCR (qPCR), plaque assay, and immunohistochemistry and for alpha/beta interferon (IFN-alpha/beta) levels and phosphorylation of interferon regulatory factors 3 and 7 (IRF-3 and -7) in brain homogenates by enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. TRIF-/- and IPS-1(-/-) mice had higher mortality rates than WT mice (P = 0.02 and P = 0.09, respectively). Viral antigens were more disseminated throughout the brain, correlating with a significant increase in brain viral load for TRIF-/- (days 5 to 9) and IPS-1(-/-) (days 7 and 9) mice compared to results for the WT. IFN-beta production was reduced in brain homogenates of TRIF-/- and IPS-1(-/-) mice on day 5 compared to results for the WT, whereas IFN-alpha levels were increased on day 7 in TRIF-/- mice. Phosphorylation levels of IRF-3 and IRF-7 were decreased in TRIF-/- and IPS-1(-/-) mice, respectively. These data suggest that both the TRIF and IPS-1 signaling pathways are important for the control of HSV replication in the brain and survival through IFN-beta production.