Association of Mutations in Toll-like Receptor 2 Signaling Genes With Fulminant Form of Hepatitis B-Related Acute Liver Failure
Association of Mutations in Toll-like Receptor 2 Signaling Genes With Fulminant Form of Hepatitis B-Related Acute Liver Failure
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Toll 样受体 2 信号基因突变与暴发性乙型肝炎相关急性肝衰竭的关联
DOI：
10.1093/infdis/jix097
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发表时间：
2017-04-15
影响因子：
6.4
通讯作者：
Zhang, Xinxin
中科院分区：
文献类型：
--
作者：
Han, Yue;Gu, Leilei;Zhang, Xinxin
背景暴发型乙型肝炎相关急性肝衰竭（FHB-ALF）是急性B型肝炎病毒（HBV）感染的一种罕见但高度致命的结局。据我们所知，其相关的宿主因素尚未研究。为了鉴定FHB-ALF发病机制中功能相关的生物学途径（8），对源自10个不相关病例的外显子组测序的罕见病例特异性变体的数据集进行途径富集分析。使用312例HBV疾病对照验证了已识别途径中的关键变异。对Toll样受体（TLR）2基因（TLR 2）变异体的机制进行了体外和体内研究。TLR信号通路高度富集，在10例病例中的9例中发现了相关变体。值得注意的是，在2例无关病例中发现了一种罕见的杂合单核苷酸变异，导致TLR 2中的F679 I突变。体外分析表明F679 I导致功能丧失。在杂合子和纯合子TLR 2基因敲除小鼠中，注射HBV复制子质粒导致比野生型小鼠更显著的丙氨酸转氨酶升高和肝脏坏死性炎症。机制分析表明，减少调节性T细胞的百分比，在后xtlR 2敲除小鼠。TLR 2信号传导在FHB-ALF患者中很可能受损。罕见的病例特异性TLR 2变异的复发强烈提示HBV感染中暴发的机制贡献。
Background. The fulminant form of hepatitis B-related acute liver failure (FHB-ALF) is a rare but highly fatal outcome of acute hepatitis B virus (HBV) infection. Its related host factors have not been studied to our knowledge.Methods. To identify functionally relevant biological pathway(8) in FHB-ALF pathogenesis, pathway enrichment analysis was conducted on a data set of rare case-specific variants derived from exomic sequencing of 10 unrelated cases. Key variants in identified pathways were validated using 312 controls with HBV disease. Mechanistic studies of a recurrent Toll-like receptor (TLR) 2 gene (TLR2) variant were performed in vitro and in vivo.Results. The TLR signaling pathway was highly enriched, with associated variants found in 9 of the 10 cases. Notably, a rare heterozygous single-nucleotide variation causing F679I mutation in TLR2 was identified in 2 unrelated cases. In vitro analysis demonstrated F679I to cause loss of function. In both heterozygous and homozygous TLR2 knockout mice, injection of HBV replicon plasmid resulted in more prominent alanine aminotransferase elevations and hepatic necroinflammation than in wild-type mice. Mechanistic analyses demonstrated reduced regulatory T-cell percentages in postexposure TLR2 knockout mice.Conclusions. TLR2 signaling is very likely impaired in patients with FHB-ALF. The recurrence of rare case-specific TLR2 variant strongly suggests mechanistic contribution to fulminancy in HBV infection.