Utility of Humanized BLT Mice for Analysis of Dengue Virus Infection and Antiviral Drug Testing
Utility of Humanized BLT Mice for Analysis of Dengue Virus Infection and Antiviral Drug Testing
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DOI：
10.1128/jvi.03085-13
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发表时间：
2014-02-01
影响因子：
5.4
通讯作者：
Ploss, Alexander
中科院分区：
文献类型：
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作者：
Frias-Staheli, Natalia;Dorner, Marcus;Ploss, Alexander
登革病毒(DENV)是一种影响全球数百万人的潜在威胁生命的疾病的原因。缺乏模仿人类DENV感染症状的小动物模型，减缓了对病毒发病机制的理解以及治疗和疫苗的开发。在这里，我们使用人源化的“骨髓肝胸腺”(BLT)小鼠作为免疫学研究的模型，并测试它们在抗病毒化合物临床前测试中的适用性。人免疫系统(HIS)BLT-NOD/SCID小鼠静脉接种DENV-2低传代临床分离株，可引起持续性病毒血症和淋巴及非淋巴器官的白细胞感染。此外，DENV感染增加了血清细胞因子水平，并诱导了DENV-2中和人IgM抗体。在DENV感染的树突状细胞重新刺激后，体内启动的T细胞被激活并获得效应功能。DENV的腺苷核苷抑制剂在同时或感染后2天给药时减少循环病毒RNA，模拟了一种潜在的治疗人类DENV感染的方案。综上所述，我们证明BLT小鼠对临床分离的DENV易感，可启动病毒特异性适应性免疫反应，并对抗病毒药物治疗有反应。尽管模型还需要进一步改进，但BLT小鼠是研究DENV感染和发病机制以及进行候选药物和疫苗临床前测试的合适平台。
Dengue virus (DENV) is the cause of a potentially life-threatening disease that affects millions of people worldwide. The lack of a small animal model that mimics the symptoms of DENV infection in humans has slowed the understanding of viral pathogenesis and the development of therapies and vaccines. Here, we investigated the use of humanized "bone marrow liver thymus" (BLT) mice as a model for immunological studies and assayed their applicability for preclinical testing of antiviral compounds. Human immune system (HIS) BLT-NOD/SCID mice were inoculated intravenously with a low-passage, clinical isolate of DENV-2, and this resulted in sustained viremia and infection of leukocytes in lymphoid and nonlymphoid organs. In addition, DENV infection increased serum cytokine levels and elicited DENV-2-neutralizing human IgM antibodies. Following restimulation with DENV-infected dendritic cells, in vivo-primed T cells became activated and acquired effector function. An adenosine nucleoside inhibitor of DENV decreased the circulating viral RNA when administered simultaneously or 2 days postinfection, simulating a potential treatment protocol for DENV infection in humans. In summary, we demonstrate that BLT mice are susceptible to infection with clinical DENV isolates, mount virus-specific adaptive immune responses, and respond to antiviral drug treatment. Although additional refinements to the model are required, BLT mice are a suitable platform to study aspects of DENV infection and pathogenesis and for preclinical testing of drug and vaccine candidates.