Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis
Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis
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DOI：
10.1073/pnas.0308057100
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发表时间：
2004-02-03
影响因子：
11.1
通讯作者：
Finberg, RW
中科院分区：
文献类型：
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作者：
Kurt-Jones, EA;Chan, M;Finberg, RW
感染单纯疱疹病毒1（HSV-1）的人类新生儿发展为三种不同感染模式之一：（i）限于皮肤、眼或口的感染;（ii）CNS感染;或（iii）播散性感染。播散型通常累及肝脏、肾上腺和肺，类似于细菌性脓毒症的临床表现。HSV-1感染新生儿的症状谱表明炎性细胞因子在疾病的发病机制中起重要作用。最近的研究表明，Toll样受体（TLR）可能在诱导炎症细胞因子应答病毒中起重要作用。TLR是Toll的哺乳动物同源物，Toll是一种对宿主防御感染至关重要的果蝇蛋白。TLR与细菌、病毒或真菌组分的结合导致细胞因子和其他抗微生物产物的产生和释放。在这里，我们证明了TLR 2介导的炎症细胞因子对HSV-1的反应，通过使用转染的细胞系和敲除小鼠。对感染小鼠的研究表明，HSV-1在TLR 2（-/-）小鼠中诱导了钝化的细胞因子应答。单核细胞趋化蛋白1趋化因子在TLR 2（-/-）小鼠中的脑水平显著低于野生型或TLR 4（-/-）小鼠。与野生型小鼠相比，TLR 2（-/-）小鼠的死亡率降低。TLR 2（-/-）小鼠与野生型和TLR 4（-/-）小鼠在单核细胞趋化蛋白1诱导、脑炎症或死亡率方面的差异无法根据病毒水平来解释。因此，这些研究表明TLR 2介导的细胞因子对HSV-1的应答对宿主有害。
Human neonates infected with herpes simplex virus 1 (HSV-1) develop one of three distinct patterns of infection: (i) infection limited to the skin, eye or mouth; (ii) infection of the CNS; or (iii) disseminated infection. The disseminated form usually involves the liver, adrenal gland, and lung, and resembles the clinical picture of bacterial sepsis. This spectrum of symptoms in HSV-1-infected neonates suggests that inflammatory cytokines play a significant role in the pathogenesis of the disease. Recent studies suggest that the Toll-like receptors (TLRs) may play an important role in the induction of inflammatory cytokines in response to viruses. TLRs are mammalian homologues of Toll, a Drosophila protein that is essential for host defense against infection. Engagement of TLRs by bacterial, viral, or fungal components leads to the production and release of cytokines and other antimicrobial products. Here, we demonstrate that TLR2 mediates the inflammatory cytokine response to HSV-1 by using both transfected cell lines and knockout mice. Studies of infected mice revealed that HSV-1 induced a blunted cytokine response in TLR2(-/-) mice. Brain levels of monocyte chemoattractant protein 1 chemokine were significantly lower in TLR2(-/-) mice than in either wild-type or TLR4(-/-) mice. TLR2(-/-) mice had reduced mortality compared with wild-type mice. The differences between TLR2(-/-) mice and both wild-type and TLR4(-/-) mice in the induction of monocyte chemoattractant protein 1, brain inflammation, or mortality could not be accounted for on the basis of virus levels. Thus, these studies suggest the TLR2-mediated cytokine response to HSV-1 is detrimental to the host.