Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
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DOI：
10.1073/pnas.0711942105
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发表时间：
2008-06-10
影响因子：
11.1
通讯作者：
Yuen, Kwok-Yung
中科院分区：
文献类型：
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作者：
Zheng, Bo-Jian;Chan, Kwok-Wah;Yuen, Kwok-Yung
人类感染甲型H5 N1流感病毒的死亡率可超过80%。高死亡率及其对神经氨酸酶抑制剂奥司他韦的不良反应归因于不受控制的病毒诱导的细胞因子风暴。我们用1，000 LD 50的流感A/Vietnam/1194/04攻击BALB/c小鼠。在单独或联合扎那韦、塞来昔布、吉非罗齐和美沙拉秦治疗的感染小鼠中记录了存活率、体重、组织病理学、炎症标志物、病毒载量、T淋巴细胞计数和中和抗体应答。为了模拟真实生活场景，在病毒攻击后48小时开始处理。与扎那米韦单药治疗相比，扎那米韦、塞来昔布和美沙拉嗪三联治疗组的生存率（P = 0.02）、生存时间（P < 0.02）和炎症标志物（P < 0.01）均有显著改善。扎那米韦与或不与免疫调节剂降低病毒载量的程度相似。当单独使用单个药物时，观察到生存期无显著延长。三联治疗组的CD 4+和CD 8 + T淋巴细胞水平也显著升高，肺部炎症也较轻。扎那米韦单独降低病毒载量，但不能降低炎症和死亡率。在扎那米韦中添加塞来昔布和美沙拉嗪的生存益处可能是由于它们在减少细胞因子功能障碍和防止细胞凋亡方面的协同作用。在H5 N1感染患者的随机对照治疗试验中，应考虑神经氨酸酶抑制剂与这些免疫调节剂的组合。
The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P = 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated-with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4(+) and CD8(+) T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis. Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.