Biophysical constraints of influenza neuraminidase evolution

流感神经氨酸酶进化的生物物理限制

• 批准号: 10654846
• 负责人: Nicholas C. Wu
• 金额: $ 51.23万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-28 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654846
• 关键词: Amino Acid Substitution; Amino Acids; Antibodies; Attention; Biochemical; Biological Assay; Biology; Biophysical Process; Biophysics; Cessation of life; Data; Development; Effectiveness; Evolution; Genetic; Genetic Epistasis; Glycoproteins; Goals; Hemagglutinin; Human; Immunity; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza Hemagglutinin; Knowledge; Maps; Measures; Molecular; Mutation; Neuraminidase; Pathway interactions; Play; Population; Proteins; Public Health; Research; Role; Shapes; Statistical Models; Surface; Surface Antigens; Update; Vaccines; Viral; Viral Proteins; Virus Replication; biophysical model; biophysical properties; experimental study; fitness; global health; influenza epidemic; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; insight; interdisciplinary approach; interest; mutant; mutation screening; next generation; porcine model; seasonal influenza; structural biology; transmission process; vaccine development; viral fitness

PROJECT SUMMARY Seasonal influenza epidemic causes 3-5 million infections and 250,000 to 500,000 deaths every year. While seasonal influenza vaccine is available and being constantly updated, its effectiveness is often hampered by the rapid antigenic drift of circulating strains. As a result, a major goal of influenza research is to develop a more effective vaccine. Nevertheless, the poor ability to forecast the evolution of influenza virus poses a huge challenge in influenza vaccine development. Consequently, understanding how the evolutionary trajectories of influenza virus are being shaped can significantly benefit public health. Influenza virus has two surface antigens, namely hemagglutinin (HA) and neuraminidase (NA). While influenza vaccine development has traditionally focused on targeting the HA, NA has received increasing attention as an effective vaccine target in recent years. Evolution of NA is under several biophysical constraints including protein stability, surface expression, and enzymatic activity. These biophysical constraints determine not only the fitness effects of individual mutations, but also how these fitness effects vary in the presence of other mutations (i.e. epistasis). In fact, epistasis has been a main obstacle in evolution forecast since epistasis can lead to opposite fitness effects of the same mutation in different influenza strains. This proposed study will use innovative high- throughput experiments to systematically probe the fitness effects of all possible amino-acid mutations on NA and map epistatic interactions that are involved in the natural evolution of NA. In addition, the molecular mechanisms of epistasis will be characterized by biochemical and structural biology approaches. Statistical modeling will further be applied to quantify the relationships between biophysical constraints of NA and viral fitness. The results will comprehensively reveal the biophysical principles that govern the mutational fitness effects and epistatic interactions in influenza NA, and hence its evolutionary trajectories in natural evolution. This proposed study will therefore promote the construction of a unifying biophysical model to accurately forecast the evolution of influenza virus, which will in turn facilitate the development of next-generation influenza vaccines.

项目摘要 季节性流感流行病每年引起3-500万感染和250,000至500,000人死亡。尽管 可以使用季节性流感疫苗并不断更新，其有效性通常受到阻碍 循环菌株的快速抗原漂移。结果，流感研究的主要目标是开发 更有效的疫苗。然而，预测流感病毒演变的不良能力构成了巨大的 流感疫苗开发中的挑战。因此，了解如何的进化轨迹 正在形成流感病毒可以极大地使公共卫生受益。流感病毒有两个表面 抗原，即血凝素（HA）和神经氨酸酶（NA）。而流感疫苗的开发有 传统上专注于针对HA，NA作为有效的疫苗目标受到了越来越多的关注 近年来。 Na的演变在几种生物物理约束下，包括蛋白质稳定性，表面 表达和酶活性。这些生物物理约束不仅决定了 个体突变，但这些适应性在存在其他突变（即上毒）的情况下会有所不同。 实际上，上毒一直是进化预测的主要障碍 在不同流感菌株中相同突变的影响。这项拟议的研究将使用创新的高 吞吐量实验，以系统地探测所有可能的氨基酸突变对Na的适应性影响 以及与Na的自然演化有关的MAP上的同义相互作用。另外，分子 上位性的机制将以生化和结构生物学方法为特征。统计 建模将进一步应用来量化Na和病毒的生物物理约束之间的关系 健康。结果将全面揭示控制突变适应性的生物物理原理 流感NA中的影响和上毒相互作用，因此在自然进化中的进化轨迹。 因此，这项拟议的研究将促进统一的生物物理模型的构建以准确 预测流感病毒的演变，这反过来又有助于下一代发展 流感疫苗。

项目成果

Mutational fitness landscape of human influenza H3N2 neuraminidase.

• DOI: 10.1016/j.celrep.2022.111951
• 发表时间: 2023-01-31
• 期刊: Cell reports
• 影响因子: 8.8