Cross-protective potential of anti-nucleoprotein human monoclonal antibodies against lethal influenza A virus infection
Cross-protective potential of anti-nucleoprotein human monoclonal antibodies against lethal influenza A virus infection
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DOI：
10.1099/jgv.0.000518
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发表时间：
2016-09-01
影响因子：
3.8
通讯作者：
Ono, Etsuro
中科院分区：
文献类型：
--
作者：
Fujimoto, Yoshikazu;Tomioka, Yukiko;Ono, Etsuro
核蛋白（NP）具有在甲型流感病毒中高度保守的区域，因此一直是开发通用流感疫苗的目标病毒蛋白之一。预计人类或人源化抗体将可用于病毒感染的预防、先发制人和急性治疗。然而，目前尚不清楚抗NP人抗体是否可以提供针对流感病毒感染的保护作用。在这项研究中，我们培育了表达来自感染 H5N1 高致病性禽流感 (HPAI) 病毒的患者淋巴细胞的抗 NP 人单克隆抗体的转基因小鼠，并进行了实验感染，以检查抗 NP 抗体对哺乳动物高致死率的 H5N1 HPAI 病毒感染的抗病毒作用。表达超过 1 mg ml(-1) 的抗 NP 人单克隆抗体的转基因小鼠系显示出对 H5N1 病毒感染的显着抵抗力。此外，还证实了对对小鼠具有强致病性的H1N1亚型感染的抵抗力。尽管转基因小鼠中表达的抗 NP mAb 不能中和病毒，但 mAb 可以与位于受感染细胞表面的 NP 结合。这些结果表明，非中和性抗 NP 人单克隆抗体可能诱导间接抗病毒作用，例如抗体依赖性细胞毒性或补体依赖性细胞毒性。总而言之，这些结果表明，抗 NP 人单克隆抗体在针对体内致命流感病毒感染的异亚型保护中发挥着重要作用。
The nucleoprotein (NP) possesses regions that are highly conserved among influenza A viruses, and has therefore been one of the target viral proteins for development of a universal influenza vaccine. It has been expected that human or humanized antibodies will be made available for the prophylaxis, pre-emptive and acute treatment of viral infection. However, it is still unclear whether anti-NP human antibody can confer protection against influenza virus infection. In this study, we generated transgenic mice expressing anti-NP human mAbs derived from lymphocytes of a patient infected with H5N1 highly pathogenic avian influenza (HPAI) virus, and experimental infections were conducted to examine antiviral effects of the anti-NP antibodies against H5N1 HPAI viral infections with a high fatality rate in mammals. Transgenic mouse lines expressing the anti-NP human mAbs at more than 1 mg ml(-1) showed marked resistance to H5N1 virus infections. In addition, resistance to infection with an H1N1 subtype that shows strong pathogenicity to mice was also confirmed. Although the anti-NP mAbs expressed in the transgenic mice did not neutralize the virus, the mAbs could bind to NP located on the surface of infected cells. These results suggested a possibility that the non-neutralizing anti-NP human mAbs could induce indirect antiviral effects, such as antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Taken together, these results demonstrated that anti-NP human mAbs play an important role in heterosubtypic protection against lethal influenza virus infections in vivo.