Loss in lung volume and changes in the immune response demonstrate disease progression in African green monkeys infected by small-particle aerosol and intratracheal exposure to Nipah virus

Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that emerged in the late 1990s in Malaysia and has since been identified as the cause of sporadic outbreaks of severe febrile disease in Bangladesh and India. NiV infection is frequently associated with severe respiratory or neurological disease in infected humans with transmission to humans through inhalation, contact or consumption of NiV contaminated foods. In the work presented here, the development of disease was investigated in the African Green Monkey (AGM) model following intratracheal (IT) and, for the first time, small-particle aerosol administration of NiV. This study utilized computed tomography (CT) and magnetic resonance imaging (MRI) to temporally assess disease progression. The host immune response and changes in immune cell populations over the course of disease were also evaluated. This study found that IT and small-particle administration of NiV caused similar disease progression, but that IT inoculation induced significant congestion in the lungs while disease following small-particle aerosol inoculation was largely confined to the lower respiratory tract. Quantitative assessment of changes in lung volume found up to a 45% loss in IT inoculated animals. None of the subjects in this study developed overt neurological disease, a finding that was supported by MRI analysis. The development of neutralizing antibodies was not apparent over the 8–10 day course of disease, but changes in cytokine response in all animals and activated CD8+ T cell numbers suggest the onset of cell-mediated immunity. These studies demonstrate that IT and small-particle aerosol infection with NiV in the AGM model leads to a severe respiratory disease devoid of neurological indications. This work also suggests that extending the disease course or minimizing the impact of the respiratory component is critical to developing a model that has a neurological component and more accurately reflects the human condition.

尼帕病毒（Nipah Virus，NiV）是一种副黏病毒，隶属于亨尼帕病毒属，于20世纪90年代末在马来西亚首次被发现，此后被证实为孟加拉国与印度散发性重症发热性疾病暴发的病原体。尼帕病毒感染常导致感染者出现严重呼吸道或神经系统疾病，人类可通过吸入、接触或食用受尼帕病毒污染的食物而感染。本研究以非洲绿猴（African Green Monkey，AGM）为模型，探究其经气管内（intratracheal，IT）接种以及首次采用的小颗粒气溶胶途径接种尼帕病毒后的疾病发生发展过程。本研究利用计算机断层扫描（computed tomography，CT）与磁共振成像（magnetic resonance imaging，MRI）对疾病进程进行时序性动态评估，同时对疾病进程中的宿主免疫应答及免疫细胞群的动态变化进行了检测。研究发现，气管内接种与小颗粒气溶胶接种尼帕病毒的疾病进程相似，但气管内接种会引发肺部显著充血，而小颗粒气溶胶接种所致病变主要局限于下呼吸道。对肺容积变化的定量评估显示，气管内接种组动物的肺容积最高可下降45%。本研究所有受试对象均未出现显性神经系统疾病，该结果得到磁共振成像分析的验证。在8~10天的疾病进程中，未检测到中和抗体的产生，但所有受试动物的细胞因子应答变化以及活化CD8阳性T细胞数量的改变均提示细胞介导免疫已被激活。本研究证实，在非洲绿猴模型中，气管内与小颗粒气溶胶接种尼帕病毒均可引发重症呼吸道疾病，但无神经系统症状。本研究同时提示，若要构建兼具神经系统病变、且更贴近人类感染真实情况的尼帕病毒感染模型，需延长疾病进程或减轻呼吸道病变的影响。