State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China.
State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine, Guangzhou Medical University, Guangzhou 510180, China.
Viruses. 2019 Mar 22;11(3):292. doi: 10.3390/v11030292.
Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed PB2-K526R is present in 80% of Indonesian H5N1 human isolates, which lack the more common PB2-E627K substitution. Testing the hypothesis that this mutation may prime avian H5N1 virus for human infection, we showed that: (1) K526R is rarely found in avian influenza viruses but was identified in H5N1 viruses 2⁻3 years after the virus emerged in Indonesia, coincident with the emergence of H5N1 human infections in Indonesia; (2) K526R is required for efficient replication of Indonesia H5N1 virus in mammalian cells in vitro and in vivo and reverse substitution to 526K in human isolates abolishes this ability; (3) Indonesian H5N1 virus, which contains K526R-PB2, is stable and does not further acquire E627K following replication in infected mice; and (4) virus containing K526R-PB2 shows no fitness deficit in avian species. These findings illustrate an important mechanism in which a host adaptive mutation that predisposes avian H5N1 virus towards infecting humans has arisen with the virus becoming prevalent in avian species prior to human infections occurring. A similar mechanism is observed in the Qinghai-lineage H5N1 viruses that have caused many human cases in Egypt; here, E627K predisposes towards human infections. Surveillance should focus on the detection of adaptation markers in avian strains that prime for human infection.
与其他受影响地区相比，印度尼西亚和埃及发生了更多的人感染 H5N1 病毒的情况，据推测，在这些地方，存在特定的病毒因素导致人类感染禽流感 H5N1 病毒。我们之前曾表明，80%的印度尼西亚 H5N1 人类分离株存在 PB2-K526R 突变，而这些病毒缺乏更常见的 PB2-E627K 取代。为了检验该突变可能使禽流感 H5N1 病毒更容易感染人类的假设，我们进行了如下研究：（1）K526R 在禽流感病毒中很少见，但在印度尼西亚出现病毒后 2-3 年内的 H5N1 病毒中被发现，与印度尼西亚 H5N1 人类感染的出现时间一致；（2）K526R 是印度尼西亚 H5N1 病毒在哺乳动物细胞中体外和体内高效复制所必需的，而在人类分离株中反向取代为 526K 则会削弱这种能力；（3）含有 K526R-PB2 的印度尼西亚 H5N1 病毒在感染小鼠后是稳定的，不会进一步获得 E627K 取代；（4）含有 K526R-PB2 的病毒在禽类中没有表现出适应性缺陷。这些发现说明了一个重要的机制，即一个使禽流感 H5N1 病毒更容易感染人类的宿主适应性突变，在病毒在禽类中变得普遍之前就已经出现，从而导致了人类感染的发生。在导致埃及发生多起人类感染的青海系 H5N1 病毒中也观察到了类似的机制；在这里，E627K 使病毒更容易感染人类。监测应侧重于检测使禽类病毒更容易感染人类的适应标记。
