Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection
Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection
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DOI：
10.1128/jvi.00275-17
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发表时间：
2017-08-01
影响因子：
5.4
通讯作者：
Rockx, Barry
中科院分区：
文献类型：
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作者：
Escaffre, Olivier;Saito, Tais B.;Rockx, Barry
尼帕病毒（NiV）是一种人畜共患的新型副粘病毒，可引起人类致命的呼吸道疾病或脑炎。尽管许多努力，NiV诱导的急性肺损伤（ALI）的分子机制仍不清楚。我们先前表明，NiV在NOD-SCID/γ小鼠的人肺移植物中复制到高滴度，导致强烈的炎症反应。有趣的是，这些小鼠可以通过骨髓，肝脏和胸腺（BLT）重建方法进行人类免疫系统重建，除了肺组织移植，提供了一个现实的模型来研究人类呼吸道病毒感染。在这里，我们的特点NiV孟加拉国株（NiV-B）感染的人肺移植物从人类免疫系统重建的小鼠，以确定整体效果的免疫细胞对NiV的肺发病机制。我们表明，NiV-B复制到高滴度在人肺移植物，并引起类似的细胞病变的影响，而不考虑人白细胞在小鼠中的存在。然而，人类免疫系统干扰病毒在肺移植物中的传播，通过白细胞迁移到肺移植物的小气道和肺泡来对感染做出反应，并加速肺移植物中的氧化应激。此外，人白细胞的存在增加了调节炎症流入感染和组织损伤部位的细胞因子和趋化因子的表达。这些结果推进了我们对免疫系统如何限制NiV传播和促进ALI的理解，并为确定治疗靶点提供了信息。重要信息尼帕病毒（NiV）是一种新出现的副粘病毒，可引起人类致命的呼吸道和神经系统疾病。关于NiV在人肺中的发病机制，只有有限的数据可用，并且先天免疫应答和NiV对急性肺损伤（ALI）的相对贡献仍然未知。在人类免疫系统重建的小鼠模型中使用人肺移植物，我们表明NiV孟加拉国株诱导肺移植物中的细胞病变与患者中描述的病变相似，而与供体来源或白细胞的存在无关。然而，人类免疫系统干扰病毒传播，通过小气道和肺泡区域中的白细胞浸润对感染作出反应，诱导氧化应激，并触发细胞因子和趋化因子的产生，所述细胞因子和趋化因子调节白细胞对感染作出反应的炎症流入。了解白细胞如何与NiV相互作用并在人肺异种移植物中引起ALI对于确定治疗靶点至关重要。
Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/gamma mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.