Gao P, Watanabe S, Ito T, Goto H, Wells K, McGregor M, Cooley A J, Kawaoka Y
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
J Virol. 1999 Apr;73(4):3184-9. doi: 10.1128/JVI.73.4.3184-3189.1999.
An H5N1 avian influenza A virus was transmitted to humans in Hong Kong in 1997. Although the virus causes systemic infection and is highly lethal in chickens because of the susceptibility of the hemagglutinin to furin and PC6 proteases, it is not known whether it also causes systemic infection in humans. The clinical outcomes of infection in Hong Kong residents ranged widely, from mild respiratory disease to multiple organ failure leading to death. Therefore, to understand the pathogenesis of influenza due to these H5N1 isolates, we investigated their virulence in mice. The results identified two distinct groups of viruses: group 1, for which the dose lethal for 50% of mice (MLD50) was between 0.3 and 11 PFU, and group 2, for which the MLD50 was more than 10(3) PFU. One day after intranasal inoculation of mice with 100 PFU of group 1 viruses, the virus titer in lungs was 10(7) PFU/g or 3 log units higher than that for group 2 viruses. Both types of viruses had replicated to high titers (>10(6) PFU/g) in the lungs by day 3 and maintained these titers through day 6. More importantly, only the group 1 viruses caused systemic infection, replicating in nonrespiratory organs, including the brain. Immunohistochemical analysis demonstrated the replication of a group 1 virus in brain neurons and glial cells and in cardiac myofibers. Phylogenetic analysis of all viral genes showed that both groups of Hong Kong H5N1 viruses had formed a lineage distinct from those of other viruses and that genetic reassortment between H5N1 and H1 or H3 human viruses had not occurred. Since mice and humans harbor both the furin and the PC6 proteases, we suggest that the virulence mechanism responsible for the lethality of influenza viruses in birds also operates in mammalian hosts. The failure of some H5N1 viruses to produce systemic infection in our model indicates that multiple, still-to-be-identified, factors contribute to the severity of H5N1 infection in mammals. In addition, the ability of these viruses to produce systemic infection in mice and the clear differences in pathogenicity among the isolates studied here indicate that this system provides a useful model for studying the pathogenesis of avian influenza virus infection in mammals.
1997年，一种H5N1甲型禽流感病毒在香港传播给了人类。尽管该病毒会引发全身性感染，且由于血凝素对弗林蛋白酶和PC6蛋白酶敏感，在鸡群中具有高致死性，但尚不清楚它是否也会在人类中引发全身性感染。香港居民感染后的临床结果差异很大，从轻度呼吸道疾病到导致死亡的多器官衰竭。因此，为了解这些H5N1分离株所致流感的发病机制，我们研究了它们在小鼠中的毒力。结果确定了两组不同的病毒：第1组，半数致死剂量（MLD50）在0.3至11个空斑形成单位（PFU）之间；第2组，MLD50大于10³ PFU。用100 PFU的第1组病毒经鼻接种小鼠一天后，肺中的病毒滴度为10⁷ PFU/g，比第2组病毒高3个对数单位。两种病毒在第3天时在肺中均复制到高滴度（>10⁶ PFU/g），并在第6天维持这些滴度。更重要的是，只有第1组病毒引发了全身性感染，在包括脑在内的非呼吸器官中复制。免疫组织化学分析表明，第1组病毒在脑神经元、神经胶质细胞和心肌纤维中复制。对所有病毒基因的系统发育分析表明，两组香港H5N1病毒均形成了一个与其他病毒不同的谱系，且H5N1与H1或H3人类病毒之间未发生基因重配。由于小鼠和人类均含有弗林蛋白酶和PC6蛋白酶，我们认为导致禽流感病毒在鸟类中致死的毒力机制在哺乳动物宿主中也起作用。在我们的模型中，一些H5N1病毒未能引发全身性感染，这表明多种尚未确定的因素导致了H5N1在哺乳动物中感染的严重性。此外，这些病毒在小鼠中引发全身性感染的能力以及此处研究的分离株在致病性上的明显差异表明，该系统为研究禽流感病毒在哺乳动物中的发病机制提供了一个有用的模型。
