Highly conserved motifs in NS1 and PB1-F2 proteins of highly pathogenic avian influenza viruses and their functionalities in virulence, immune responses and pathological alterations like acute lung injury (ALI)

高致病性禽流感病毒 NS1 和 PB1-F2 蛋白中高度保守的基序及其在毒力、免疫反应和急性肺损伤 (ALI) 等病理改变中的功能

• 批准号: 237780743
• 负责人: Dr. Eike-Roman Hrincius
• 金额: --
• 依托单位: The University of Tennessee Health Science Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237780743?language=en
• 关键词: Highly; conserved; motifs; NS1; PB1

As estimated by the World Health Organization, infections of the respiratory tract are responsible for more than 6 percent of all deaths worldwide. Importantly, among all pathogens having the capability to infect the respiratory tract, influenza A viruses (IAV) are among the most common and devastating. In addition to millions of hospitalizations and thousands of deaths, these pathogens lead to enormous economic losses during the seasonal influenza each year. Even more worrisome, IAV have the potential to cause pandemic outbreaks with several million victims, such as the Spanish flu outbreak in 1918 and IAV are discussed as potential causative agent for upcoming life-threatening pandemics. The zoonotic potential of IAV is fundamental for the occurrence of pandemic outbreaks in humans and the ongoing, sporadic transmission of highly pathogenic avian IAV (HPAI) of the subtype H5N1 to humans since 1997. The high case fatality rate of 60%, emphasizes the need to understand the biology of HPAI infection of humans. To understand this high case fatality rate, multiple approaches focusing on different viral proteins have been conducted. Beside the contribution of the hemagglutinin protein of HPAI to their virulence and finally transmission, the polymerase proteins have been studied for their role in increasing replication efficiency of H5N1 IAV. Less effort has been put into study of the non-structural proteins NS1 and PB1-F2 to this point. Both proteins carry immune modulatory and interferon antagonistic properties and are described as virulence determinants. In general, amino-acid motifs, which are differentially present in seasonal human and HPAI came into focus of interest for understanding the severeness of HPAI infections. Regarding the NS1 protein, a SH3 binding motif (aa212-217) is present in almost all avian IAV isolates with a special position of H5N1 isolates in contrast to seasonal human IAV lacking this motif. In the context of PB1-F2, four amino acids (pro-inflammatory motif; L62, R75, R79 and L82) have been identified as contributor to cytokine release and inflammatory responses and are highly present in avian IAV, including a high prevalence in human H5N1 isolates.In this study, the impact of the depicted motifs in NS1 and PB1-F2 on virulence of HPAI, modulation of immune responses and finally immune pathology and acute lung injury in different hosts (avian and mammalian) will be broadly investigated. Understanding the basal mechanisms of HPAI virulence in humans and the impact of these motifs potentially strengthen the ability of more guided surveillance and set up of additional treatment options for HPAI infections.

据世界卫生组织估计，呼吸道感染占全球死亡人数的6%以上。重要的是，在所有能够感染呼吸道的病原体中，甲型流感病毒（IAV）是最常见和最具破坏性的。除了数百万人住院治疗和数千人死亡外，这些病原体每年在季节性流感期间导致巨大的经济损失。更令人担忧的是，IAV有可能导致数百万受害者的大流行爆发，例如1918年的西班牙流感爆发，IAV被讨论为即将到来的威胁生命的大流行病的潜在病原体。IAV的人畜共患病潜力是人类大流行爆发的发生和自1997年以来H5 N1亚型高致病性禽IAV（HPAI）向人类的持续、零星传播的基础。60%的高病死率强调了需要了解人类感染HPAI的生物学。为了理解这种高病死率，已经进行了针对不同病毒蛋白的多种方法。除了HPAI的血凝素蛋白对其毒力和最终传播的贡献之外，还研究了聚合酶蛋白在增加H5 N1 IAV复制效率中的作用。目前对非结构蛋白NS 1和PB 1-F2的研究较少。这两种蛋白质都具有免疫调节和干扰素拮抗特性，并被描述为毒力决定因素。一般来说，季节性人类和HPAI中差异存在的氨基酸基序成为理解HPAI感染的致病性的关注焦点。关于NS 1蛋白，SH 3结合基序（aa 212 -217）存在于几乎所有禽IAV分离株中，与缺乏该基序的季节性人IAV相反，H5 N1分离株具有特殊位置。在PB 1-F2的背景下，四个氨基酸（促炎基序; L 62、R75、R79和L 82）已被鉴定为细胞因子释放和炎症反应的贡献者，并且在禽类IAV中高度存在，包括在人H5 N1分离株中的高流行率。免疫反应的调节以及不同宿主（禽类和哺乳动物）的免疫病理学和急性肺损伤将被广泛研究。了解人类HPAI毒力的基本机制以及这些基序的影响可能会加强更多指导性监测的能力，并为HPAI感染提供额外的治疗方案。