He Wenhui, Ren Bijie, Mao Fengfeng, Jing Zhiyi, Li Yunfei, Liu Yang, Peng Bo, Yan Huan, Qi Yonghe, Sun Yinyan, Guo Ju-Tao, Sui Jianhua, Wang Fengchao, Li Wenhui
Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
PLoS Pathog. 2015 Apr 22;11(4):e1004840. doi: 10.1371/journal.ppat.1004840. eCollection 2015 Apr.
Hepatitis D virus (HDV) is the smallest virus known to infect human. About 15 million people worldwide are infected by HDV among those 240 million infected by its helper hepatitis B virus (HBV). Viral hepatitis D is considered as one of the most severe forms of human viral hepatitis. No specific antivirals are currently available to treat HDV infection and antivirals against HBV do not ameliorate hepatitis D. Liver sodium taurocholate co-transporting polypeptide (NTCP) was recently identified as a common entry receptor for HDV and HBV in cell cultures. Here we show HDV can infect mice expressing human NTCP (hNTCP-Tg). Antibodies against critical regions of HBV envelope proteins blocked HDV infection in the hNTCP-Tg mice. The infection was acute yet HDV genome replication occurred efficiently, evident by the presence of antigenome RNA and edited RNA species specifying large delta antigen in the livers of infected mice. The resolution of HDV infection appears not dependent on adaptive immune response, but might be facilitated by innate immunity. Liver RNA-seq analyses of HDV infected hNTCP-Tg and type I interferon receptor 1 (IFNα/βR1) null hNTCP-Tg mice indicated that in addition to induction of type I IFN response, HDV infection was also associated with up-regulation of novel cellular genes that may modulate HDV infection. Our work has thus proved the concept that NTCP is a functional receptor for HDV infection in vivo and established a convenient small animal model for investigation of HDV pathogenesis and evaluation of antiviral therapeutics against the early steps of infection for this important human pathogen.
丁型肝炎病毒（HDV）是已知感染人类的最小病毒。在全球2.4亿感染其辅助病毒乙型肝炎病毒（HBV）的人群中，约有1500万人感染了HDV。丁型病毒性肝炎被认为是人类病毒性肝炎最严重的形式之一。目前尚无特异性抗病毒药物可用于治疗HDV感染，且抗HBV的抗病毒药物并不能改善丁型肝炎。肝牛磺胆酸钠共转运多肽（NTCP）最近被确定为HDV和HBV在细胞培养中的共同进入受体。在此，我们表明HDV可以感染表达人NTCP（hNTCP-Tg）的小鼠。针对HBV包膜蛋白关键区域的抗体可阻断hNTCP-Tg小鼠中的HDV感染。感染是急性的，但HDV基因组复制有效发生，感染小鼠肝脏中存在反基因组RNA和编码大δ抗原的编辑RNA种类证明了这一点。HDV感染的消退似乎不依赖于适应性免疫反应，但可能由先天免疫促进。对HDV感染的hNTCP-Tg小鼠和I型干扰素受体1（IFNα/βR1）缺失的hNTCP-Tg小鼠进行肝脏RNA测序分析表明，除了诱导I型干扰素反应外，HDV感染还与可能调节HDV感染的新型细胞基因上调有关。因此，我们的工作证明了NTCP是HDV体内感染的功能性受体这一概念，并建立了一个方便的小动物模型，用于研究HDV发病机制和评估针对这种重要人类病原体感染早期阶段的抗病毒治疗方法。
