HA fusion properties as a determinant of influenza transmission and pathogenicity

描述（由申请人提供）：甲型流感病毒（IAV）向新宿主的有效传播取决于多种因素。劈裂激活和膜融合特性是重要的，但被忽视的特性，IAV血凝素（HA）蛋白可能影响传播。自然环境中遇到的蛋白酶对HA裂解激活的效率可能会影响病毒的感染性、稳定性和致病性，HA介导的融合发生的pH值可能对自然界中iav的稳定性和传播性具有广泛的影响。在自然和跨物种传播周期中，iav暴露于高度不同的选择压力，这可能需要进化具有不同稳定性表型的HA蛋白。在已确定的16种血凝素亚型中，在人群中确定的唯一血凝素亚型是H1、H2和H3，源自上个世纪的四次大流行：H1N1（1918年）、H2N2（1957年）、H3N2（1968年）和H1N1（2009年）。尽管具有H5和H7 HA亚型的病毒已被证明具有高死亡率，但由于种内传播效率低下，它们尚未在人群中站稳脚跟。对不同HA亚型可用晶体结构的分析显示出明显的结构差异。这些结构差异是将HA亚型分为两组的基础：第1组和第2组。当前应用的目的是检查16种HA亚型之间的表型差异，通过检查组特异性残基在介导酸诱导的亚稳定HA向稳定的融合结构过渡过程中的不稳定中的作用。本申请中概述的研究将为所有16种HA亚型的蛋白酶裂解活化和膜融合特性提供首次大规模、详细的评估。此外，还将研究HA介导的膜融合发生的pH值变化的表型效应，包括具有酸稳定型与酸不稳定型HA蛋白的iav的环境持久性和稳定性，以及在鸟类和哺乳动物物种中的传播效率。了解所有16种亚型的HA蛋白的表型特征，以及自然发生的和群体特定序列变异的作用，对于我们获得关于跨物种传播的便利性和人类中新病毒出现的信息至关重要。

DESCRIPTION (provided by applicant): The efficient transmission of influenza A virus (IAV) to new hosts is dependent on multiple factors. Cleavage-activation and membrane fusion characteristics are significant but overlooked properties of the IAV hemagglutinin (HA) protein that may influence transmission. The efficiency of HA cleavage-activation by proteases encountered in natural environments may impact virus infectivity, stability, and pathogenicity, and the pH at which HA-mediated fusion occurs may have broad implications for the stability and transmissibility of IAVs in nature. IAVs are exposed to highly varied selective pressures during natural and cross-species transmission cycles, which might necessitate the evolution of HA proteins having different stability phenotypes. Of the 16 delineated HA subtypes, the only HA subtypes to become established in the human population are H1, H2, and H3, as derived from the four major pandemics within the last century: H1N1 (1918), H2N2 (1957), H3N2 (1968), and H1N1 (2009). Although viruses having H5 and H7 HA subtypes have been shown to infect with high mortality rates, they have yet to gain a foothold in the human population due to inefficient intra-species transmission. Analysis of the available crystal structures of different HA subtypes have revealed marked structural variations. These structural differences are the basis for the classification of HA subtypes into two groups: group 1 and group 2. The aim of the current application is to examine phenotypic differences between the 16 HA subtypes by examining the role of group-specific residues in mediating the acid-induced destabilization of the meta-stable HA during its transition to a stable, fusogenic structure. The studies outlined in this application will provide the first large-scale, detailed evaluation of the protease cleavage-activation and membrane fusion properties for all 16 HA subtypes. In addition, the phenotypic effects of variations in the pH at which HA-mediated membrane fusion occurs will be examined with regard to the environmental persistence and stability of IAVs having acid-stable versus acid-labile HA proteins, as well as the efficiency of transmission in avian and mammalian species. Understanding the phenotypic characteristics of HA proteins representative of all 16 subtypes, as well as the role of both naturally occurring and group specific sequence variations, is essential if we are to derive information regarding the ease of cross-species transmission and the emergence of novel viruses in humans. PUBLIC HEALTH RELEVANCE: Influenza virus is a major public health threat to all sectors of the population that yields serious and deleterious social and economic consequences. Understanding the molecular factors that alter the efficiency of influenza infection in animal and human hosts is essential to understanding how new viruses may affect humans.