Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus.
Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus.
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DOI：
10.1016/j.chom.2008.09.012
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发表时间：
2008-11-13
影响因子：
30.3
通讯作者：
Boshoff C
中科院分区：
文献类型：
--
作者：
Lagos D;Vart RJ;Gratrix F;Westrop SJ;Emuss V;Wong PP;Robey R;Imami N;Bower M;Gotch F;Boshoff C
Toll样受体4（TLR 4）参与抗人类疱疹病毒的免疫尚未得到证实。我们发现，卡波西肉瘤疱疹病毒（KSHV），一种人类致癌病毒感染的内皮细胞，导致TLR 4表达的快速抑制。这是一种免疫逃逸机制，因为TLR 4介导针对KSHV的先天免疫。在体外，缺乏TLR 4的细胞对KSHV感染更敏感，而TLR 4的激活保护细胞免受感染。在体内，携带突变型TLR 4等位基因的HIV-1感染者似乎更可能患有多中心Castleman病，这是一种与KSHV复制增强相关的淋巴细胞增生。KSHV结构蛋白和KSHV编码的vGPCR激活ERK在TLR 4下调中起关键作用，而KSHV vIRF 1也有助于这种作用。我们的研究结果揭示了TLR 4在抗疱疹病毒的先天免疫中的作用，并表明TLR 4激动剂在治疗KSHV相关肿瘤中的潜在用途。
The involvement of Toll-like receptor 4 (TLR4) in immunity against human herpesviruses has not been previously demonstrated. We show that infection of endothelial cells with Kaposi sarcoma herpesvirus (KSHV), a human oncogenic virus, leads to rapid suppression of TLR4 expression. This is a mechanism of immune escape as TLR4 mediates innate immunity against KSHV. In vitro, cells lacking TLR4 are more susceptible to KSHV infection, whereas activation of TLR4 protects cells from infection. In vivo, HIV-1-infected individuals carrying a mutant TLR4 allele appear more likely to have multicentric Castleman's disease, a lymphoproliferation associated with enhanced KSHV replication. ERK activation by KSHV structural proteins and the KSHV-encoded vGPCR plays a key role in the TLR4 downregulation, whereas the KSHV vIRF1 also contributes to this effect. Our findings reveal a role for TLR4 in innate immunity against herpesviruses and suggest the potential use of TLR4 agonists for the treatment of KSHV-related neoplasms.
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