HA fusion properties as a determinant of influenza transmission and pathogenicity

描述（由申请方提供）：甲型流感病毒（IAV）向新宿主的有效传播取决于多种因素。裂解激活和膜融合特性是IAV血凝素（HA）蛋白的重要但被忽视的特性，可能会影响传播。在自然环境中遇到的蛋白酶的HA切割-活化的效率可能影响病毒感染性、稳定性和致病性，并且HA介导的融合发生的pH可能对自然界中IAV的稳定性和可传播性具有广泛的影响。IAV在自然和跨物种传播周期中暴露于高度变化的选择压力，这可能需要进化具有不同稳定性表型的HA蛋白。在所描述的16种HA亚型中，在人群中建立的唯一HA亚型是H1、H2和H3，其源自上个世纪的四次主要流行病：H1N1（1918）、H2 N2（1957）、H3 N2（1968）和H1N1（2009）。尽管具有H5和H7 HA亚型的病毒已显示出高死亡率的感染，但由于物种内传播效率低，它们尚未在人群中站稳脚跟。对不同HA亚型的可用晶体结构的分析揭示了显著的结构变化。这些结构差异是将HA亚型分为两组的基础：组1和组2。本申请的目的是通过检查组特异性残基在介导酸诱导的亚稳态HA不稳定化（在其转变为稳定的融合结构期间）中的作用来检查16种HA亚型之间的表型差异。本申请中概述的研究将首次对所有16种HA亚型的蛋白酶切割-活化和膜融合特性进行大规模详细评价。此外，HA介导的膜融合发生的pH值的变化的表型效应将检查关于具有酸稳定与酸不稳定HA蛋白的IAV的环境持久性和稳定性，以及在禽类和哺乳动物物种中的传播效率。了解代表所有16种亚型的HA蛋白的表型特征，以及天然存在的和组特异性序列变异的作用，如果我们要获得关于跨物种传播的便利性和人类中新病毒的出现的信息，是必不可少的。 公共卫生相关性：流感病毒是对所有人群的重大公共卫生威胁，产生严重和有害的社会和经济后果。了解改变动物和人类宿主中流感感染效率的分子因素对于了解新病毒如何影响人类至关重要。

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.