Stepwise release of biologically active HMGB1 during HSV-2 infection.
Stepwise release of biologically active HMGB1 during HSV-2 infection.
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DOI：
10.1371/journal.pone.0016145
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发表时间：
2011-01-19
期刊：
影响因子：
3.7
通讯作者：
Gozlan J
中科院分区：
文献类型：
--
作者：
Borde C;Barnay-Verdier S;Gaillard C;Hocini H;Maréchal V;Gozlan J
高迁移率族蛋白1（HMGB 1）是一种主要的内源性危险信号，在脓毒性和无菌性应激期间触发炎症和免疫。HMGB 1最近成为各种感染性疾病发病机制中的关键可溶性因子，但其在疱疹病毒感染期间的行为尚不清楚。因此，我们研究了HMGB 1在HSV-2感染上皮HEC-1细胞过程中的动力学和生物学效应。尽管在感染过程中HMGB 1基因表达的转录关闭，但HMGB 1蛋白的细胞内池仍不受影响，表明其显着的稳定性。然而，HMGB 1的动力学在感染的细胞中被深度修饰。而病毒增殖是伴随着细胞凋亡和HMGB 1保留在染色质上，随后释放HMGB 1观察到响应HSV-2介导的坏死。重要的是，细胞外HMGB 1具有生物活性。事实上，来自HSV-2感染细胞的含HMGB 1的上清液诱导来自鼠或人来源的成纤维细胞迁移，并从潜伏感染的T淋巴细胞中重新激活HIV-1。这些作用与HMGB 1特异性相关，因为它们被HMGB 1或中和性抗HMGB 1抗体阻断，并通过TLR 2和晚期糖基化终产物受体（EGFR）介导。最后，我们表明生殖器HSV-2活动性感染也促进HMGB 1在体内的释放，加强了我们的实验数据的临床相关性。这些观察结果将HMGB 1作为HSV-2生殖器感染过程中的重要作用者，特别是在HSV-HIV合并感染的情况下。
High mobility group box 1 protein (HMGB1) is a major endogenous danger signal that triggers inflammation and immunity during septic and aseptic stresses. HMGB1 recently emerged as a key soluble factor in the pathogenesis of various infectious diseases, but nothing is known of its behaviour during herpesvirus infection. We therefore investigated the dynamics and biological effects of HMGB1 during HSV-2 infection of epithelial HEC-1 cells. Despite a transcriptional shutdown of HMGB1 gene expression during infection, the intracellular pool of HMGB1 protein remained unaffected, indicating its remarkable stability. However, the dynamics of HMGB1 was deeply modified in infected cells. Whereas viral multiplication was concomitant with apoptosis and HMGB1 retention on chromatin, a subsequent release of HMGB1 was observed in response to HSV-2 mediated necrosis. Importantly, extracellular HMGB1 was biologically active. Indeed, HMGB1-containing supernatants from HSV-2 infected cells induced the migration of fibroblasts from murine or human origin, and reactivated HIV-1 from latently infected T lymphocytes. These effects were specifically linked to HMGB1 since they were blocked by glycyrrhizin or by a neutralizing anti-HMGB1 antibody, and were mediated through TLR2 and the receptor for Advanced Glycation End-products (RAGE). Finally, we show that genital HSV-2 active infections also promote HMGB1 release in vivo, strengthening the clinical relevance of our experimental data. These observations target HMGB1 as an important actor during HSV-2 genital infection, notably in the setting of HSV-HIV co-infection.
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影响因子：
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作者：
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