Mouse models of dengue virus infection for vaccine testing.
Mouse models of dengue virus infection for vaccine testing.
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DOI：
10.1016/j.vaccine.2015.09.112
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发表时间：
2015-12-10
期刊：
影响因子：
5.5
通讯作者：
Barrett AD
中科院分区：
文献类型：
--
作者：
Sarathy VV;Milligan GN;Bourne N;Barrett AD
登革热是一种由蚊子传播的疾病，由四种血清学和遗传相关的病毒（称为 DENV-1 至 DENV-4）引起。全球热带和亚热带地区每年约有 3.9 亿例感染，因此迫切需要一种有效的疫苗来对抗登革热。从历史上看，登革热研究的一个主要障碍是开发一种合适的小动物感染模型，在不存在神经系统疾病的情况下模拟人类疾病的特征，而神经系统疾病是早期小鼠模型的标志。免疫受损小鼠感染模型的最新进展导致在缺乏干扰素-α/β受体（IFN-α/β R）和干扰素-γ受体（IFN-γR）的 AG129 小鼠中开发出致命的 DENV-2、DENV-3 和 DENV-4 模型。这些模型模仿了人类登革热疾病的许多标志性特征，例如病毒血症、血小板减少、血管渗漏和细胞因子风暴。重要的是，AG129 小鼠会出现致命的、急性的、具有全身病毒载量的播散性感染，这是典型登革热疾病的特征。受感染的 AG129 小鼠产生针对 DENV 的抗体反应，并且通过 DENV 免疫血清的被动和母体转移建立了抗体依赖性增强 (ADE) 模型。已经采取了几个步骤来完善 DENV 小鼠模型。通过体内外周传代产生的病毒会发生替换，从而使用较小的接种物提供毒力表型。由于 IFN 信号传导在 DENV 免疫中发挥重要作用，因此需要产生细胞免疫反应的小鼠，但在 DENV 易感性和完整免疫之间取得平衡很复杂。使用单缺陷 IFN-α/βR 小鼠在 DENV-2 感染方面取得了巨大进步，条件敲除可能提供额外的方法来提供包括病毒毒力和宿主免疫在内的全景视图。最终，DENV AG129 小鼠模型产生可重复的致死率，并提供多种疾病参数来评估候选疫苗的保护作用。
Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the Interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines.
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影响因子：
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