Aerosol exposure to intermediate size Nipah virus particles induces neurological disease in African green monkeys.
Aerosol exposure to intermediate size Nipah virus particles induces neurological disease in African green monkeys.
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DOI：
10.1371/journal.pntd.0006978
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发表时间：
2018-11
影响因子：
3.8
通讯作者：
Holbrook MR
中科院分区：
文献类型：
--
作者：
Hammoud DA;Lentz MR;Lara A;Bohannon JK;Feuerstein I;Huzella L;Jahrling PB;Lackemeyer M;Laux J;Rojas O;Sayre P;Solomon J;Cong Y;Munster V;Holbrook MR
尼帕病毒（NiV）感染可导致人类严重的呼吸道或神经系统疾病。NiV的传播已被证明通过接触病毒污染的污染物或食用受污染的食物发生。以前的结果使用非洲绿色猴（AGM）模型的NiV感染确定方面的感染，虽然类似于人类，不完全重演疾病。先前的研究还证明了与人类NiV感染不一致的几乎一致的致死率。在这些研究中，使用中等粒度（7μm）的气溶胶暴露通过促进病毒在上呼吸道沉积来模拟潜在的人体暴露。计算机断层扫描评价发现一些动物发生肺实质疾病，包括实变、毛玻璃样阴影和反应性淋巴结病。尽管缺乏神经系统体征，磁共振成像在三只动物中发现了明显的脑病变，与先前报道的NiV感染患者相似。尸检时收集的组织的免疫学表征表明局部肺部炎症反应，肺中巨噬细胞水平升高，但神经系统反应有限。这些数据提供了第一个明确的证据表明，神经参与AGM，概括人类疾病。随着更能代表人类疾病的疾病模型的发展，这些数据表明，AGM中的NiV感染可能适用于评估针对病毒诱导的神经发病机制的治疗对策。开发治疗人类疾病的有效治疗方法需要了解感染因子诱导的疾病过程。历史上，针对高致病性病毒的医学对策的发展需要使用一致致死的动物模型。虽然这种方法在某些方面是有用的，但它通常不能提供疾病过程的真实指示。在这里介绍的工作中，方法是使用一种病毒暴露方法，该方法模拟了人类暴露的潜在途径，并使用了可能更能代表人类接受的剂量。使用这种方法和先进的医学成像技术，我们能够证明一个扩展的疾病过程与混合呼吸系统和神经系统疾病一样，在人类中看到的。这项研究还发现，肺部感染的反应是炎症性的，尽管有明显的病变证据，但脑部疾病是有限的。这些数据支持模拟人类疾病的动物模型的开发，并允许识别针对疾病过程而不仅仅是病毒的潜在治疗方法。
Nipah virus (NiV) infection can lead to severe respiratory or neurological disease in humans. Transmission of NiV has been shown to occur through contact with virus contaminated fomites or consumption of contaminated food. Previous results using the African green monkey (AGM) model of NiV infection identified aspects of infection that, while similar to humans, don’t fully recapitulate disease. Previous studies also demonstrate near uniform lethality that is not consistent with human NiV infection. In these studies, aerosol exposure using an intermediate particle size (7μm) was used to mimic potential human exposure by facilitating virus deposition in the upper respiratory tract. Computed tomography evaluation found some animals developed pulmonary parenchymal disease including consolidations, ground-glass opacities, and reactive adenopathy. Despite the lack of neurological signs, magnetic resonance imaging identified distinct brain lesions in three animals, similar to those previously reported in NiV-infected patients. Immunological characterization of tissues collected at necropsy suggested a local pulmonary inflammatory response with increased levels of macrophages in the lung, but a limited neurologic response. These data provide the first clear evidence of neurological involvement in the AGM that recapitulates human disease. With the development of a disease model that is more representative of human disease, these data suggest that NiV infection in the AGM may be appropriate for evaluating therapeutic countermeasures directed at virus-induced neuropathogenesis. The development of effective therapeutic approaches to the treatment of human diseases requires an understanding of the disease process induced by an infectious agent. Historically the development of medical countermeasures for highly pathogenic viruses required the use of a uniformly lethal animal model. While this approach is useful in some regards, it frequently does not provide a true indication of the disease process. In the work presented here, the approach was to use a virus exposure method that mimicked a potential route of human exposure and used a dose that might be more representative of one a human would receive. Using this method and advanced medical imaging techniques, we were able to demonstrate an extended disease course with mixed respiratory and neurological disease like that seen in humans. This study also found that the response to infection in the lungs was inflammatory and that the disease in the brain was limited despite clear evidence of lesions. These data support the development of animal models that mimic human disease and allow for the identification of potential therapeutic approaches that target the disease process rather than only the virus.
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