Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species.
Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species.
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DOI：
10.1371/journal.ppat.1006270
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发表时间：
2017-03
期刊：
影响因子：
6.7
通讯作者：
Manicassamy B
中科院分区：
文献类型：
--
作者：
Tundup S;Kandasamy M;Perez JT;Mena N;Steel J;Nagy T;Albrecht RA;Manicassamy B
高致病性禽流感H5 N1病毒在哺乳动物中异常高毒力的细胞和分子机制仍不清楚。在这里，我们调查，如果H5 N1病毒的细胞嗜性是一个决定因素，增强在哺乳动物物种的毒力。我们通过将microRNA靶位点整合到病毒基因组中，利用细胞类型特异性microRNA表达，设计了具有有限细胞嗜性的H5 N1病毒。通过miR-126限制H5 N1在内皮细胞中的复制改善了疾病症状，防止了全身性病毒传播并限制了死亡率，尽管与对照病毒感染的小鼠相比，在肺中显示出相似的病毒复制峰值水平。同样，限制H5 N1在内皮细胞中的复制导致疾病症状的改善和病毒在雪貂中的传播减少。我们的研究表明，H5 N1感染内皮细胞导致细胞因子的过度产生，并降低肺中内皮屏障的完整性，最终导致血管渗漏和病毒性肺炎。重要的是，我们的研究表明，需要一种靶向病毒成分，抑制宿主免疫反应，并提高内皮屏障完整性的组合疗法，用于治疗高致病性H5 N1病毒感染。在健康的个体中，季节性流感病毒感染的症状是轻微的，感染在4-7天内被清除。然而，高致病性禽流感病毒（H5 N1）的感染可能很严重，即使在健康成年人中也经常导致致命的肺炎。虽然已知病毒和宿主因素在加速疾病进展中发挥作用，但H5 N1病毒高毒力的分子机制尚未完全了解。在这项研究中，我们设计了不能在内皮细胞中复制的禽流感H5 N1病毒，并在小鼠和雪貂中评估了疾病症状。我们的研究表明，H5 N1感染内皮细胞导致严重疾病和受感染动物死亡，部分原因是血管内皮细胞受损，导致液体渗漏到肺部（肺炎）。
The cellular and molecular mechanisms underpinning the unusually high virulence of highly pathogenic avian influenza H5N1 viruses in mammalian species remains unknown. Here, we investigated if the cell tropism of H5N1 virus is a determinant of enhanced virulence in mammalian species. We engineered H5N1 viruses with restricted cell tropism through the exploitation of cell type-specific microRNA expression by incorporating microRNA target sites into the viral genome. Restriction of H5N1 replication in endothelial cells via miR-126 ameliorated disease symptoms, prevented systemic viral spread and limited mortality, despite showing similar levels of peak viral replication in the lungs as compared to control virus-infected mice. Similarly, restriction of H5N1 replication in endothelial cells resulted in ameliorated disease symptoms and decreased viral spread in ferrets. Our studies demonstrate that H5N1 infection of endothelial cells results in excessive production of cytokines and reduces endothelial barrier integrity in the lungs, which culminates in vascular leakage and viral pneumonia. Importantly, our studies suggest a need for a combinational therapy that targets viral components, suppresses host immune responses, and improves endothelial barrier integrity for the treatment of highly pathogenic H5N1 virus infections. In healthy individuals, the symptoms of seasonal influenza virus infection are mild and the infection is cleared within 4–7 days. However, infection with highly pathogenic avian influenza virus (H5N1) can be severe and often results in fatal pneumonia even in healthy adults. While it is known that both viral and host factors play a role in enhanced disease progression, the molecular mechanisms for the high virulence of H5N1 virus are not completely understood. In this study, we engineered avian influenza H5N1 viruses incapable of replicating in endothelial cells and evaluated disease symptoms in mice and ferrets. Our studies show that H5N1 infection of endothelial cells causes severe disease and death of infected animals in part due to the damage of endothelial cells lining the blood vessels, which results in leakage of fluid into the lungs (pneumonia).