HMGBI mediates HAdV-7 infection-induced pulmonary inflammation in mice
HMGBI mediates HAdV-7 infection-induced pulmonary inflammation in mice
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HMGBI 介导 HAdV-7 感染诱导的小鼠肺部炎症
DOI：
10.1016/j.bbrc.2018.03.145
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发表时间：
2018
影响因子：
3.1
通讯作者：
Liu Enmei
中科院分区：
文献类型：
--
作者：
Tang Zhengzhen;Zang Na;Fu Yangxi;Ye Zhixu;Chen Sisi;Mo Shi;Ren Luo;Liu Enmei
人腺病毒（HAdV）是儿童常见的呼吸道病原体，目前尚无安全有效的治疗方法。特别是HAdV 7型（HAdV-7）可引起严重的小儿肺炎，后遗症和死亡率高。临床数据和动物实验表明，HAdV-7诱导的肺炎促进细胞坏死，释放大量炎症介质。近年来，坏死细胞释放的高迁移率族蛋白B1（HMGB 1）蛋白已被证明在几种病毒感染中发挥重要作用。HAdV-7感染A549细胞12 h后，HMGB 1在培养上清中的表达水平逐渐升高，在体内，HAdV-7感染3 d后，BALF中HMGB 1的表达水平和肺组织中HMGB 1 mRNA的表达水平显著升高。在HMGB 1受体基因中，TLR-4和TLR-9的表达增加，晚期糖基化终产物受体（AGEs）的表达也增加。有趣的是，NF-κB水平也随之增加。相反，当HMGB 1被阻断时，肺组织的病理评分、炎症介质水平和病毒拷贝数均显著降低;此外，HMGB 1相关的信号通路分子TLR-4、TLR-9、TNF-α和NF-κB也降低。我们的结论是，HMGB 1促进HAdV-7的复制，并通过TLR-4、TLR-9和TLR-4受体激活NF-κB，刺激炎症介质的释放，促进腺病毒病理学。因此，HMGB 1可作为HAdV-7感染的治疗靶点。
Human adenovirus (HAdV) is a common respiratory pathogen in children, with no safe and effective treatment currently available. HAdV type 7 (HAdV-7), in particular, causes severe pediatric pneumonia with a high incidence of sequelae and mortality. Clinical data and animal experiments suggest that HAdV-7-induced pneumonia promotes cell necrosis, releasing a large number of inflammatory mediators. In recent years, the high mobility group box-1 (HMGB1) protein, released by necrotic cells, has been shown to play important roles in several viral infections. Here, we show that HMGB1 levels gradually increased in the media supernatants of HAdV-7 infected A549 cells, starting at 12 h post-infection.In vivo, HMGB1 levels in BALF and mRNA levels in lung tissues significantly increased after 3 days of HAdV-7 infection. Among the HMGB1 receptor genes, TLR-4 and TLR-9 expression increased, and so did the receptor for advanced glycation end-products (RAGE). Interestingly, NF-κB levels also increased concomitantly. Conversely, when HMGB1 was blocked, the pathological scores from lung tissues, inflammatory mediator levels, and viral copy number all were reduced significantly; in addition, HMGB1-related signaling pathway molecules, namely TLR-4, TLR-9, RAGE, and NF-κB were also reduced. We conclude that HMGB1 promotes HAdV-7 replication and signals through TLR-4, TLR-9, and RAGE receptors to activate NF-κB, stimulating the release of inflammatory mediators and contributing to adenoviral pathology. Thus, HMGB1 could be used as a therapeutic target in HAdV-7 infection.