Contribution of Segment 3 to the Acquisition of Virulence in Contemporary H9N2 Avian Influenza Viruses.
Contribution of Segment 3 to the Acquisition of Virulence in Contemporary H9N2 Avian Influenza Viruses.
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DOI：
10.1128/jvi.01173-20
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发表时间：
2020-09-29
影响因子：
5.4
通讯作者：
Iqbal M
中科院分区：
文献类型：
--
作者：
Clements AL;Sealy JE;Peacock TP;Sadeyen JR;Hussain S;Lycett SJ;Shelton H;Digard P;Iqbal M
禽流感病毒，如H9 N2，对全世界的家禽生产造成巨大的经济损失，并被认为是潜在的大流行威胁。了解这些病毒如何在其自然宿主中进化是有效控制策略的关键。在中东和南亚，一种较老的H9 N2病毒株已被适应性更强的新毒株所取代。在这里，我们采取代表性的病毒，并调查这种“健身”的遗传基础。病毒中的一个突变导致了更大的适应性，使当代H9 N2病毒在细胞和鸡中的高生长成为可能。调节这种变化的基因突变是在病毒PA蛋白，病毒聚合酶基因的一部分，有助于病毒复制以及病毒的辅助功能，然而，我们发现，健身效果是特别是由于蛋白质聚合酶活性的变化。H9 N2禽流感病毒（AIV）在亚洲、中东和非洲大部分地区的家禽中传播。这些病毒对家禽生产系统造成巨大的经济损失，并在其自身和新型人畜共患病病毒（例如H7N9）的产生中构成人畜共患病威胁。近年来，观察到H9 N2病毒进一步适应了鸡家禽，变得更高传染性，并导致更高的发病率和死亡率。在这里，我们调查这种增加的毒力的分子基础，比较从20世纪90年代的病毒和当代现场应变。现代病毒在各种系统中复制到更高的滴度，并且这种差异映射到PA和PA-X蛋白共享的核酸内切酶结构域的位置26处的单个氨基酸多态性。这种变化是导致复制增加和发病率和死亡率升高的原因，沿着在鸡中观察到的组织嗜性延长。虽然PA K26 E的变化与体外PA-X蛋白的宿主细胞关闭活性增加相关，但它不能被阻断PA-X表达的移码位点突变所覆盖，因此PA-X活性增加不能解释复制表型的差异。相反，这表明这些差异是由于对PA功能的微妙影响。这项工作深入了解了H9 N2和其他禽流感病毒的持续进化和家禽适应，并帮助我们了解该领域惊人的发病率和死亡率，以及这些病毒迅速扩大的地理范围。重要性禽流感病毒，如H9 N2，对全世界的家禽生产造成巨大的经济损失，并被认为是潜在的大流行威胁。了解这些病毒如何在其自然宿主中进化是有效控制策略的关键。在中东和南亚，一种较老的H9 N2病毒株已被适应性更强的新毒株所取代。在这里，我们采取代表性的病毒，并调查这种“健身”的遗传基础。病毒中的一个突变导致了更大的适应性，使当代H9 N2病毒在细胞和鸡中的高生长成为可能。调节这种变化的基因突变是在病毒PA蛋白，病毒聚合酶基因的一部分，有助于病毒复制以及病毒的辅助功能，然而，我们发现，健身效果是特别是由于蛋白质聚合酶活性的变化。
Avian influenza viruses, such as H9N2, cause huge economic damage to poultry production worldwide and are additionally considered potential pandemic threats. Understanding how these viruses evolve in their natural hosts is key to effective control strategies. In the Middle East and South Asia, an older H9N2 virus strain has been replaced by a new reassortant strain with greater fitness. Here, we take representative viruses and investigate the genetic basis for this “fitness.” A single mutation in the virus was responsible for greater fitness, enabling high growth of the contemporary H9N2 virus in cells, as well as in chickens. The genetic mutation that modulates this change is within the viral PA protein, a part of the virus polymerase gene that contributes to viral replication as well as to virus accessory functions—however, we find that the fitness effect is specifically due to changes in the protein polymerase activity. H9N2 avian influenza viruses (AIVs) circulate in poultry throughout much of Asia, the Middle East, and Africa. These viruses cause huge economic damage to poultry production systems and pose a zoonotic threat both in their own right and in the generation of novel zoonotic viruses, for example, H7N9. In recent years, it has been observed that H9N2 viruses have further adapted to gallinaceous poultry, becoming more highly transmissible and causing higher morbidity and mortality. Here, we investigate the molecular basis for this increased virulence, comparing a virus from the 1990s and a contemporary field strain. The modern virus replicated to higher titers in various systems, and this difference mapped to a single amino acid polymorphism at position 26 of the endonuclease domain shared by the PA and PA-X proteins. This change was responsible for increased replication and higher morbidity and mortality rates along with extended tissue tropism seen in chickens. Although the PA K26E change correlated with increased host cell shutoff activity of the PA-X protein in vitro, it could not be overridden by frameshift site mutations that block PA-X expression and therefore increased PA-X activity could not explain the differences in replication phenotype. Instead, this indicates that these differences are due to subtle effects on PA function. This work gives insight into the ongoing evolution and poultry adaptation of H9N2 and other avian influenza viruses and helps us understand the striking morbidity and mortality rates in the field, as well as the rapidly expanding geographical range seen in these viruses. IMPORTANCE Avian influenza viruses, such as H9N2, cause huge economic damage to poultry production worldwide and are additionally considered potential pandemic threats. Understanding how these viruses evolve in their natural hosts is key to effective control strategies. In the Middle East and South Asia, an older H9N2 virus strain has been replaced by a new reassortant strain with greater fitness. Here, we take representative viruses and investigate the genetic basis for this “fitness.” A single mutation in the virus was responsible for greater fitness, enabling high growth of the contemporary H9N2 virus in cells, as well as in chickens. The genetic mutation that modulates this change is within the viral PA protein, a part of the virus polymerase gene that contributes to viral replication as well as to virus accessory functions—however, we find that the fitness effect is specifically due to changes in the protein polymerase activity.