Sanada Takahiro, Tsukiyama-Kohara Kyoko, Yamamoto Naoki, Ezzikouri Sayeh, Benjelloun Soumaya, Murakami Shuko, Tanaka Yasuhito, Tateno Chise, Kohara Michinori
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24, Korimoto, Kagoshima-city, Kagoshima 890-0065, Japan; Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24, Korimoto, Kagoshima, Kagoshima 890-0065, Japan.
Biochem Biophys Res Commun. 2016 Jan 8;469(2):229-35. doi: 10.1016/j.bbrc.2015.11.121. Epub 2015 Nov 30.
The northern treeshrew (Tupaia belangeri) has been reported to be an effective candidate for animal infection model with hepatitis B virus (HBV). The objective of our study was to analyze the growth characteristics of HBV in tupaia hepatocytes and the host response to HBV infection. We established primary tupaia hepatocytes (3-6-week old tupaia) and infected them with HBV genotypes A, B and C, and all the genotypes proliferated as well as those in human primary hepatocytes (>10(5) copies/ml in culture supernatant). We next generated a chimeric mouse with tupaia liver by transplantation of tupaia primary hepatocytes to urokinase-type plasminogen activator cDNA (cDNA-uPA)/severe combined immunodeficient (SCID) mice and the replacement ratio with tupaia hepatocytes was found to be more than 95%. Infection of chimeric mice with HBV (genotypes B, C, and D) resulted in HBV-DNA level of 10(4)-10(6) copies/ml after 8 weeks of infection, which were almost similar to that in humanized chimeric mouse. In contrast, serum HBV level in adult tupaia (1-year-old tupaia) was quite low (<10(3) copies/ml). Understanding the differences in the response to HBV infection in primary tupaia hepatocytes, chimeric mouse, and adult tupaia will contribute to elucidating the mechanism of persistent HBV infection and viral eradication. Thus, T. belangeri was found to be efficient for studying the host response to HBV infection, thereby providing novel insight into the pathogenesis of HBV.
据报道，北树鼩（Tupaia belangeri）是乙型肝炎病毒（HBV）动物感染模型的有效候选者。我们研究的目的是分析HBV在树鼩肝细胞中的生长特性以及宿主对HBV感染的反应。我们建立了原代树鼩肝细胞（3 - 6周龄树鼩），并用HBV A、B和C基因型感染它们，所有基因型均能增殖，且增殖情况与人类原代肝细胞中的情况相同（培养上清液中>10⁵拷贝/ml）。接下来，我们通过将树鼩原代肝细胞移植到尿激酶型纤溶酶原激活剂cDNA（cDNA - uPA）/严重联合免疫缺陷（SCID）小鼠中，构建了具有树鼩肝脏的嵌合小鼠，发现树鼩肝细胞的替代率超过95%。用HBV（B、C和D基因型）感染嵌合小鼠8周后，HBV - DNA水平为10⁴ - 10⁶拷贝/ml，这与人类化嵌合小鼠中的情况几乎相似。相比之下，成年树鼩（1岁树鼩）的血清HBV水平相当低（<10³拷贝/ml）。了解原代树鼩肝细胞、嵌合小鼠和成年树鼩对HBV感染反应的差异将有助于阐明HBV持续感染和病毒清除的机制。因此，发现北树鼩对于研究宿主对HBV感染的反应是有效的，从而为HBV的发病机制提供了新的见解。
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