Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: implications for host range and adaptation.
Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: implications for host range and adaptation.
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DOI：
10.1371/journal.ppat.1003151
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Steinhauer DA
中科院分区：
文献类型：
--
作者：
Galloway SE;Reed ML;Russell CJ;Steinhauer DA
甲型流感病毒(IAV)HA蛋白必须被宿主细胞蛋白酶激活，才能为融合分子做好准备。因此，激活的蛋白水解酶的可用性和HA对蛋白水解酶活性的敏感性是促进病毒感染的关键因素。因此，了解各种酶对HA裂解的复杂性对于深入了解大流行病毒的出现是必要的。为了检查这些特性，我们生成了一个Ha小组，这些小组代表了在水生鸟类中流通的16个HA亚型，以及上个世纪感染人类群体的亚型的代表。我们检测了一组HA蛋白对胰酶以及人呼吸道胰酶样蛋白(HAT)和跨膜蛋白丝氨酸2(TMPRSS2)的敏感性。此外，我们还检测了它们介导膜融合的pH，因为这一特性与HA分子的稳定性有关，并影响流感病毒在自然环境中保持感染的能力。我们的结果表明，不同的HAS的切割效率可能会有很大的差异，这取决于不同的蛋白酶，并且某些HA亚型对作为融合功能激活剂的特定蛋白酶表现出严格的选择性。此外，我们发现融合的pH在不同亚型之间相差0.7pH单位，值得注意的是，我们观察到来自人类分离株的大多数HAS的融合pH低于来自相同亚型的禽类分离株的融合pH。总体而言，这些数据首次对所有IAV HA亚型的切割激活和膜融合特性进行了广谱分析，并表明可能影响宿主间传播和在新物种中建立的亚型之间存在实质性差异。IAV与严重的发病率和死亡率有关，是一种具有挑战性的公共卫生威胁，每年都会影响社会和经济福利，特别是在IAV大流行期间。虽然我们知道所有人类毒株都直接或通过中间宿主来自禽类病毒来源，但我们对在水禽中传播并有可能感染哺乳动物的16个HA亚型的表型特征知之甚少。HA膜的融合特性，以及HA的蛋白酶激活特性是融合所必需的，是IAV生态和传播的关键因素，如果我们要解释大流行病毒如何在人类中出现，就需要了解这些特性。我们通过在细胞中瞬时表达HA蛋白，检测了16种HA亚型的切割激活和膜融合特性。我们的发现表明，Has的切割能力在不同的亚型和不同的蛋白酶之间有很大的不同。此外，对每个亚型的融合pH的分析表明，HA的稳定性在亚型之间以及从不同物种分离的病毒的亚型内都有显著差异。总体而言，这些数据对寄主范围、适应潜力和在自然环境中的持久性都有影响。
The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species. IAV is associated with significant morbidity and mortality, and represents a challenging public health threat that affects social and economic welfare each year, particularly during IAV pandemics. Although we know that all human strains derive, either directly or via intermediate hosts, from avian viral sources, we know very little about the phenotypic characteristics of the 16 HA subtypes that circulate in aquatic birds and have potential to infect mammals. HA membrane fusion properties, in conjunction with the characteristics for protease activation of HA, a requirement for fusion, are critical factors involved in the ecology and transmission of IAVs, and need to be understood if we are to derive explanations for how pandemic viruses emerge in humans. We examined the cleavage-activation and membrane fusion characteristics for the 16 HA subtypes by transiently expressing HA proteins in cells. Our findings show that the cleavability of the HAs vary considerably between subtypes and depending on the protease. Additionally, analysis of the pH of fusion for each subtype showed that HA stability varied significantly among the subtypes, as well as within subtypes from viruses isolated from different species. Overall, these data have implications for host range, potential for adaptation, and persistence in natural environments.
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影响因子：
5.4
作者：
Guan, Y;Shortridge, KF;Peiris, M
通讯作者：
Peiris, M
影响因子：
3.7
作者：
GRAMBAS, S;HAY, AJ
通讯作者：
HAY, AJ
影响因子：
3.5
作者：
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影响因子：
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作者：
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通讯作者：
ALMOND, JW
DOI：
10.1126/science.1213362
发表时间：
2012-06-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Herfst S;Schrauwen EJ;Linster M;Chutinimitkul S;de Wit E;Munster VJ;Sorrell EM;Bestebroer TM;Burke DF;Smith DJ;Rimmelzwaan GF;Osterhaus AD;Fouchier RA
通讯作者：
Fouchier RA