Avian influenza H7N9 viruses: a rare second warning

Biodog

2013年在中国出现的禽流感H7N9病毒每年重新出现，造成1600多人的严重人类感染。由于这些病毒本质上是进化的，它们已经获得了一些，并且可以获得额外的毒力决定因素，从而增加了对人类的风险，强调了迫切需要在中国控制和根除H7N9病毒。
H7N9禽流感病毒（IAV）感染人类的第一个报告2013年3月来自中国[1,2]，随后在2013年有139例，47例死亡。与H5N1型禽流感病毒不同，在禽类中导致严重疾病和死亡，H7N9病毒禽流感在临床上并不显着，因此农业部门没有事先警告在家禽和活禽市场上流行的致命禽流感病毒4。自2013年以来，H7N9爆发每年都在“波浪”中复发。在5波的过程中，已经确认了1 624例包括612例死亡的人类病例，致使病死率为39％（http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_09_27_2017.pdf？u = 1） ;虽然病毒对家禽没有致病性。 2017年的第五波是最严重的，比以往任何波浪都造成了更多的人类感染（http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_09_27_2017.pdf？u = 1）。
自然界中的IAV具有巨大的多样性 - 基于两种主要病毒表面蛋白（血凝素（HA）和神经氨酸酶（NA））的抗原性，将IAV分为18个不同的HA和11个NA亚型。虽然水鸟和滨鸟是它们的天然宿主，但是这些物种的感染通常是无症状的，IAV感染的物种范围很广。相反，家禽中的IAV感染会导致一系列轻度感染（称为低致病性禽流感（LPAI）），到称为高致病性禽流感（HPAI）的严重多系统致死性感染。在18个HA亚型中，只有两个亚型HAV和H7的IAV与HPAI相关。当HA获得改变鸡病毒组织嗜性的分子改变时，HPAI病毒从自然界的LPAI病毒演化而来。在一些情况下，HPAI病毒的LPAI前体已被鉴定，而在其他情况下，通过HA序列的系统发生分析推断前体LPAI病毒。高致病性禽流感病毒具有破坏性的经济影响，就像1996年出现的H5N1型病毒所发生的一样，在世界上的一些国家已经成为流行病。虽然自2013年以来在中国引起人类感染的禽流感病毒H7N9是LPAI病毒，但人们一直担心这种病毒可能从这些流行于鸡和鸭中的大型病毒中流出。在2017年H7N9感染的第五次浪潮中，这种可能性已成为现实，已经有28人感染高致病性禽流感病毒（http://www.wpro.who.int/emerging_diseases/ai_weekly_601_wpro_20170908.pdf）。最近Shi等[5]报道了从鸡，鸭和环境中分离293株H7N9菌株的结果。他们在病毒中观察到很好的基因组多样性，并将其分为23种不同的基因型。他们从含有4种不同HA序列基序的家禽中鉴定出7种高致病性禽流感病毒，表明高致病性禽流感病毒可能来自不同的H7N9 LPAI前体。是什么驱使LPAI H7N9病毒流传4年后出现高致病性禽流感病毒？这只是一个时间和数量的问题，还是出现了允许获得高度可切割HA的基因型？具有特定HA序列基序的病毒之一是否比其他病毒具有健康优势？
高致病性禽流感H7N9病毒出现在人类公共健康方面的两个关键后果是，它们在小鼠和白鼬中实验评估的毒力，以及由病毒通过雪貂中的空气传播途径传播的能力评估的大流行潜力豚鼠6。 Shi和同事使用一个HPAI禽流感病毒检查了这些问题5。 A /安徽/ 2013/2013年HPAI H7N9病毒的毒力和传播性与LPAI原型病毒的毒力和传播性相似。在哺乳动物中复制后，禽流感病毒通常会在PB2聚合酶蛋白中发生突变7,8，这些突变与毒力增强有关，并与空气传播有关。
不出所料，从实验感染HPAI H7N9病毒的雪貂中回收到PB2蛋白中带有突变的高致病性禽流感病毒，这些病毒对小鼠是致死的。它们与A / Anhui / 1/2013 LPAI病毒一样可传播，但是在雪貂中毒性更强。这些发现与最近关于人类HPAI H7N9分离株的报道一致9。这些数据表明虽然来自家禽的高致病性禽流感H7N9病毒可能不会直接对人类造成对LPAI H7N9病毒的威胁增加，但感染人类获得PB2蛋白突变的病毒后代可能更具毒性，因此构成更大的威胁。
在重大公共卫生事件发生之前，全球公共卫生系统并不经常得到明确的警告。 HPAI H7N9病毒的出现在两个方面代表了第二个警告。首先，1996年确定了高致病性禽流感H5N1病毒10，但没有得到控制。他们现在是流行的，并继续进化和传播，并导致严重的零星感染。高致病性禽流感病毒H7N9病毒可能会沿用相同的路径，导致农业部门的重大经济代价以及零星和严重的人类感染，同时流行病传播。尽管目前的数据并不能说明HPAI H7N9病毒比LPAI病毒对人类的毒性更强11，但H7N9病毒的某些生物学特性表明它们可能比H5N1病毒具有更大的流行潜力。其次，随着高致病性禽流感病毒H7N9病毒从多个LPAI前体中出现，H7N9 LPAI病毒已经重新出现5年，并且在2017年已经演变并扩散得更为广泛。
有一次是警告，两次是教训;我们不能忽视H7N9病毒的传播，并让它们变成流行的。正如作者所指出的那样5，仅将控制措施集中在高致病性禽流感感染的鸡群上并不能解决问题，因为高致病性禽流感病毒是来源于LPAI病毒。必须从禽类中根除LPAI和HPAI H7N9病毒，并密切监测人类H7N9病毒分离株。
Avian influenza A H7N9 viruses that emerged in China in 2013 have reappeared each year, causing more than 1 600 severe human infections. As these viruses have evolved in nature, they have gained some and can gain additional virulence determinants that enhance their risk for humans, underlining the urgent need to control and eradicate H7N9 viruses in China.
The first reports of H7N9 avian influenza A virus (IAV) infections in humans came from China in March 20131,2, followed by 139 cases and 47 deaths in 20133. Unlike H5N1 avian influenza infections that caused severe illness and deaths in birds, H7N9 virus infections were clinically inapparent in birds, thus there was no prior warning from the agricultural sector of a virulent avian influenza virus circulating in poultry and live bird markets4. Each year since 2013, H7N9 outbreaks have recurred in 'waves'; over the course of 5 waves, 1 624 human cases including 612 deaths have been confirmed, resulting in a case fatality rate of 39% (http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_09_27_2017.pdf?ua=1); though the virus was not pathogenic for poultry. The 5th wave in 2017 has been the most severe and has caused more human infections than any earlier wave (http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_09_27_2017.pdf?ua=1).
There is enormous diversity in IAVs in nature - based on the antigenicity of the two major viral surface proteins, the haemagglutinin (HA) and neuraminidase (NA), IAVs are classified into 18 distinct HA and 11 NA subtypes. IAVs infect a wide range of species, though waterfowl and shorebirds are their natural hosts and infection in these species is usually asymptomatic. In contrast, IAV infections in poultry can cause a range of clinical disease from mild infection termed low pathogenic avian influenza (LPAI), to severe multisystem lethal infection that is termed highly pathogenic avian influenza (HPAI). Of the 18 HA subtypes, IAVs of only two subtypes, H5 and H7, are associated with HPAI. HPAI viruses evolve from LPAI viruses in nature when the HA acquires molecular changes that alter the tissue tropism of the virus in chickens. In some instances, the LPAI precursor of an HPAI virus has been identified and in other cases, the precursor LPAI virus is inferred by phylogenetic analysis of the HA sequence. HPAI viruses have a devastating economic impact, as has occurred with H5N1 viruses that emerged in 1996 and have become enzootic in several countries around the world. Although the avian H7N9 IAVs that have caused human infections in China since 2013 were LPAI viruses, there has been a lingering concern that an HPAI H7N9 virus could emerge from the large reservoir of these viruses circulating in chickens and ducks. In the 5th wave of H7N9 infections in 2017, this eventuality became a reality and 28 human infections with HPAI viruses have been reported (http://www.wpro.who.int/emerging_diseases/ai_weekly_601_wpro_20170908.pdf). Recently, Shi et al.5 reported their findings from a careful examination of 293 H7N9 isolates from chickens, ducks and the environment. They observed great genomic diversity among the viruses and classified them into 23 distinct genotypes. They identified 7 HPAI viruses from poultry bearing 4 different HA sequence motifs, suggesting that the HPAI viruses may have arisen from different H7N9 LPAI precursors. What drove the emergence of HPAI viruses after 4 years of LPAI H7N9 virus circulation? Was it simply a matter of time and numbers or did a genotype emerge permitting the acquisition of a highly cleavable HA? Will one of the viruses bearing a specific HA sequence motif have a fitness advantage over the others?
The two key consequences of the emergence of HPAI H7N9 viruses for human public health are their virulence, which is experimentally assessed in mice and ferrets, and pandemic potential, which is assessed by the ability of the virus to transmit by the airborne route in ferrets or guinea pigs6. Shi and colleagues examined these questions using one HPAI avian isolate5. The virulence and transmissibility of the HPAI H7N9 virus was similar to that of the LPAI prototype virus from 2013, A/Anhui/1/2013. After replication in mammals, avian influenza viruses often acquire mutations in the PB2 polymerase protein7,8 that are associated with enhanced virulence and are implicated in airborne transmission. Not surprisingly, HPAI viruses bearing mutations in the PB2 protein were recovered from ferrets that were experimentally infected with the HPAI H7N9 virus and these viruses were lethal for mice. They were as transmissible as the A/Anhui/1/2013 LPAI virus but were more virulent in ferrets. These findings are consistent with a recent report about a human HPAI H7N9 isolate9. These data suggest that while an HPAI H7N9 virus from poultry may not directly pose an increased threat to humans over LPAI H7N9 viruses, virus progeny from infected humans that have acquired mutations in the PB2 protein may be more virulent and therefore, pose a greater threat.
It is not often that the global public health system receives a recognizable warning in advance of a significant public health event. The emergence of HPAI H7N9 viruses represents a second warning in two ways. First, HPAI H5N1 viruses were identified in 199610 and were not controlled. They are now enzootic and continue to evolve and spread and cause severe sporadic infections. HPAI H7N9 viruses could well follow the same path resulting in significant economic costs for the agricultural sector and sporadic and severe human infections, with the spectre of pandemic spread. Although current data do not indicate that HPAI H7N9 viruses are more virulent for humans than their LPAI counterparts11, some biological characteristics of H7N9 viruses suggest that they may have greater pandemic potential than H5N1 viruses9. Second, H7N9 LPAI viruses have re-emerged for 5 years and have evolved and spread more widely in 2017 than in previous years, with the emergence of HPAI H7N9 viruses from more than one LPAI precursor. Once is a warning, twice is a lesson; we cannot afford to ignore the spread of H7N9 viruses and allow them to become enzootic. As the authors state5, focusing control measures only on HPAI-infected flocks will not solve the problem because HPAI viruses are derived from LPAI viruses. Both LPAI and HPAI H7N9 viruses must be eradicated from avian species and human isolates of H7N9 viruses must be monitored closely.