Simian Retrovirus 4 Induces Lethal Acute Thrombocytopenia in Japanese Macaques.
Simian Retrovirus 4 Induces Lethal Acute Thrombocytopenia in Japanese Macaques.
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猿猴逆转录病毒 4 会诱发日本猕猴致命的急性血小板减少症。
DOI：
10.1128/jvi.03611-14
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发表时间：
2015
影响因子：
5.4
通讯作者：
Miyazawa T.
中科院分区：
文献类型：
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作者：
Yoshikawa Y;Okamoto M;Sakaguchi S;Nakagawa S;Miura T;Hirai H;Miyazawa T.
2001-2002年，在京都大学灵长类研究所(KUPRI)，7只日本猕猴(Macaca Fuscata)中有6只死于出血性综合症。虽然当时的死因尚不清楚，但我们在2008-2011年的一次类似疫情中检测到了猿猴逆转录病毒4型(SRV-4)，在那次疫情中，43只日本猕猴中有42只死于出血综合征。在这项研究中，我们从一只表现出严重血小板减少症的日本猕猴身上分离出SRV-4毒株PRI-172。当接种到四只日本猕猴身上时，该分离株在37天内全部引起了严重的血小板减少症。然后，我们构建了一个具有感染性的PRI-172株的分子克隆，命名为pSR415，并将克隆衍生的病毒接种到两只日本猕猴身上。这些动物在接种后仅31天就出现了严重的血小板减少症，并从血液、骨髓和粪便中重新分离出病毒。在尸检中，我们观察到所有动物的牙龈出血和皮下出血。实时逆转录-聚合酶链式反应(RT-PCR)和免疫组织化学染色显示，SRV-4感染多种组织，尤其是消化器官，包括结肠和胃。此外，我们还鉴定了SRV-4受体为ASCT2，一种中性氨基酸转运体。ASCT2基因在多种组织中表达，SRV-4前病毒在感染猕猴体内的分布与ASCT2基因的表达水平有很好的相关性。根据这些结果，我们得出结论：KUPRI猕猴出血性综合征的病原体是SRV-4，其受体是ASCT2。在2001-2002年和2008-2011年KUPRI的两次单独暴发中，96%的日本猕猴(JM)出现了不明原因的出血性综合征。在这里，我们从一例出现血小板减少症的JM中分离出SRV-4。SRV-4分离株和一株分子克隆的SRV-4在接种病毒后37天内引起JMS严重的血小板减少。在尸检中，我们观察到所有受影响的JMS患者的牙龈出血和皮下出血，并从血液、骨髓和粪便中重新分离出SRV-4。SRV-4前病毒在组织中的分布与ASCT2的mRNA表达水平相关，我们将其确定为SRV-4受体。根据这些结果，我们认为SRV-4是库普里JMS出血性综合征的病原体。
In 2001-2002, six of seven Japanese macaques (Macaca fuscata) died after developing hemorrhagic syndrome at the Kyoto University Primate Research Institute (KUPRI). While the cause of death was unknown at the time, we detected simian retrovirus 4 (SRV-4) in samples obtained from a similar outbreak in 2008-2011, during which 42 of 43 Japanese macaques died after exhibiting hemorrhagic syndrome. In this study, we isolated SRV-4 strain PRI-172 from a Japanese macaque showing severe thrombocytopenia. When inoculated into four Japanese macaques, the isolate induced severe thrombocytopenia in all within 37 days. We then constructed an infectious molecular clone of strain PRI-172, termed pSR415, and inoculated the clone-derived virus into two Japanese macaques. These animals also developed severe thrombocytopenia in just 31 days after inoculation, and the virus was reisolated from blood, bone marrow, and stool. At necropsy, we observed bleeding from the gingivae and subcutaneous bleeding in all animals. SRV-4 infected a variety of tissues, especially in digestive organs, including colon and stomach, as determined by real-time reverse transcription-PCR (RT-PCR) and immunohistochemical staining. Furthermore, we identified the SRV-4 receptor as ASCT2, a neutral amino acid transporter. ASCT2 mRNA was expressed in a variety of tissues, and the distribution of SRV-4 proviruses in infected Japanese macaques correlated well with the expression levels of ASCT2 mRNA. From these results, we conclude that the causative agent of hemorrhagic syndrome in KUPRI Japanese macaques was SRV-4, and its receptor is ASCT2.IMPORTANCEDuring two separate outbreaks at the KUPRI, in 2001-2002 and 2008-2011, 96% of Japanese macaques (JM) that developed an unknown hemorrhagic syndrome died. Here, we isolated SRV-4 from a JM developing thrombocytopenia. The SRV-4 isolate and a molecularly cloned SRV-4 induced severe thrombocytopenia in virus-inoculated JMs within 37 days. At necropsy, we observed bleeding from gingivae and subcutaneous bleeding in all affected JMs and reisolated SRV-4 from blood, bone marrow, and stool. The distribution of SRV-4 proviruses in tissues correlated with the mRNA expression levels of ASCT2, which we identified as the SRV-4 receptor. From these results, we conclude that SRV-4 was the causative agent of hemorrhagic syndrome in JMs in KUPRI.