MECHANISTIC UNDERSTANDING OF INFLUENZA-HOST INTERACTIONS FROM A ZOONOTIC PERSPECTIVE

从人畜共患病的角度理解流感-宿主相互作用的机制

• 批准号: 10242968
• 负责人: Nicholas C. Wu
• 金额: $ 24.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242968
• 关键词: Affinity; Amino Acid Sequence; Amino Acid Substitution; Antiviral Agents; Avian Influenza A Virus; Binding; Biochemistry; Biological; Biophysical Process; Birds; Cells; Coiled-Coil Domain; Complex; Coupling; Cryoelectron Microscopy; Crystallization; Data; Disease Outbreaks; Engineering; Epidemic; Genetic; Genetic Variation; Genome; Goals; Hemagglutinin; Human; Immune; Immune Evasion; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H2N2 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N7 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Influenza A virus; Innate Immune Response; Integration Host Factors; Interferons; Intervention; Length; Maps; Mass Spectrum Analysis; Measures; Mediating; Membrane Glycoproteins; Molecular; Molecular Biology; Mutagenesis; Mutation; Neuraminidase; Outcome; Pathogenicity; Phase; Play; Population; Property; Proteins; Publishing; RNA Viruses; Recombinant Proteins; Research; Risk; Role; Species Specificity; Specificity; Structure; Systems Biology; TRIM25 gene; Technology; Tropism; Validation; Variant; Viral Proteins; Virus; Yeasts; Zoonoses; aquatic bird; base; biophysical properties; cross-species transmission; fitness; influenza virus strain; influenzavirus; insight; mortality; mutation screening; next generation sequencing; novel; pandemic disease; particle; preference; prevent; protein protein interaction; receptor; seasonal influenza; socioeconomics; structural biology; transmission process; ubiquitin-protein ligase; virus host interaction

PROJECT SUMMARY Influenza A virus is a negative-strand RNA virus and is classified into subtypes based on the antigenic properties of the two surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (NA). There are 18 known HA subtypes (H1 to H18) and 11 known NA subtypes (N1 to N11). Wild aquatic birds are the main natural reservoir for influenza A viruses. However, spillover from natural reservoirs can cause human pandemics. Three subtypes (H1N1, H2N2, and H3N2) have caused human pandemics, and two of them (H1N1 and H3N2) are presently circulating the in human population, causing seasonal outbreaks. Other subtypes found in natural reservoirs also occasionally transmit to the human population, as exemplified by H5N1, H5N6, H6N1, H7N7, H7N9, H9N2, and H10N8 viruses. These zoonotic subtypes can be highly pathogenic and have a high mortality rate (>50% of hospitalized individuals) when infecting humans. The virus- host protein-protein interaction constitutes the molecular basis of influenza pathogenicity. Many “omics” studies have explored influenza-host interactions. However, the known mechanistic details are far from comprehensive, especially regarding variation in pathogenicity across different virus subtypes and hosts. The objective of the proposed study is to understand how genetic variation in influenza virus and the host together influence pathogenicity. This proposal will focus on influenza NS1 protein, which is a major pathogenicity determinant and plays a role in host adaptation. NS1 is known to interact with many host proteins. Some of these interactions are known to be influenza subtype-dependent. In the proposed study, NS1 from two seasonal subtypes (H1N1 and H3N2) and one zoonotic subtype (H5N1) will be employed. The difference in the functional constraints of these three NS1 in human and avian cells will be interrogated by deep mutational scanning and systematic interactome analysis (K99 phase). Subsequently, biophysical characterization of NS1-TRIM25 interaction will be performed. NS1 interacts with TRIM25, which is an E3 ubiquitin ligase, to suppress the innate immune response. NS1-TRIM25 interaction is virus subtype-dependent and host-dependent. The underlying biophysical mechanism will be probed by affinity maturation and cryo- electron microscopy (K99/R00 phase). The proposed study will facilitate a detailed understanding of influenza pathogenicity and tropism from the molecular biology, genetics, evolutionary, and structural biology perspectives. More importantly, the integrative research framework developed in this study will be applicable to other influenza virus proteins, or even to proteins from other viruses.

项目摘要 流感病毒是一种阴性链RNA病毒，并根据抗原分类为亚型 两种表面糖蛋白的特性，即血凝素（HA）和神经苷酶（NA）。有18个 已知的HA亚型（H1至H18）和11个已知的Na亚型（N1至N11）。野生水生鸟是主要的 影响力病毒的天然水库。但是，来自自然储层的Spilover会导致人类 大流行。三个亚型（H1N1，H2N2和H3N2）引起了人类大流行病，其中两个 （H1N1和H3N2）目前正在人口中流传，导致季节性暴发。其他 自然储层中发现的亚型也有时也会传播给人口，例如 H5N1，H5N6，H6N1，H7N7，H7N9，H9N2和H10N8病毒。这些动物亚型可以很高 感染人类时，致病性高（> 50％的住院个体）。病毒- 宿主蛋白 - 蛋白质相互作用构成了影响力的分子基础。许多“ OMICS”研究 已经探索了影响力 - 主持人的相互作用。但是，已知的机械细节远非 全面，尤其是考虑不同病毒亚型和宿主的致病性变化。 拟议研究的目的是了解影响力病毒和 宿主共同影响致病性。该建议将集中于影响NS1蛋白，这是一个主要的 致病性确定器并在宿主适应中起作用。已知NS1与许多主机互动 蛋白质。这些相互作用中的某些相互作用依赖于actractza亚型。在拟议的研究中 将雇用来自两个季节性亚型（H1N1和H3N2）和一个人畜共患亚型（H5N1）的NS1。这 这三个NS1在人和鸟类细胞中的功能约束差异将被询问 深突变扫描和系统的相互作用分析（K99阶段）。随后，生物物理 将执行NS1-TRIM25相互作用的表征。 NS1与TRIM25相互作用，这是E3 泛素连接酶，以抑制先天的免疫反应。 NS1-TRIM25相互作用是病毒亚型依赖性 和宿主依赖。潜在的生物物理机制将通过亲和力成熟和冷冻探测 电子显微镜（K99/R00相）。拟议的研究将促进对影响力的详细理解 来自分子生物学，遗传学，进化和结构生物学的致病性和向往 观点。更重要的是，本研究中开发的综合研究框架将适用于 其他影响病毒蛋白，甚至会影响其他病毒的蛋白质。

项目成果

Sequence signatures of two public antibody clonotypes that bind SARS-CoV-2 receptor binding domain.

• DOI: 10.1038/s41467-021-24123-7
• 发表时间: 2021-06-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tan TJC;Yuan M;Kuzelka K;Padron GC;Beal JR;Chen X;Wang Y;Rivera-Cardona J;Zhu X;Stadtmueller BM;Brooke CB;Wilson IA;Wu NC
• 通讯作者: Wu NC

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure.

• DOI: 10.3390/v12091053
• 发表时间: 2020-09-22
• 期刊: Viruses
• 作者: Wu NC;Wilson IA
• 通讯作者: Wilson IA

A cross-neutralizing antibody between HIV-1 and influenza virus.

• DOI: 10.1371/journal.ppat.1009407
• 发表时间: 2021-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Lee CD;Watanabe Y;Wu NC;Han J;Kumar S;Pholcharee T;Seabright GE;Allen JD;Lin CW;Yang JR;Liu MT;Wu CY;Ward AB;Crispin M;Wilson IA
• 通讯作者: Wilson IA

A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity.

• DOI: 10.1084/jem.20200061
• 发表时间: 2020-11-02
• 期刊: The Journal of experimental medicine
• 作者: Thai E;Costa G;Weyrich A;Murugan R;Oyen D;Flores-Garcia Y;Prieto K;Bosch A;Valleriani A;Wu NC;Pholcharee T;Scally SW;Wilson IA;Wardemann H;Julien JP;Levashina EA
• 通讯作者: Levashina EA

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections.

• DOI: 10.1101/2020.03.15.993097
• 发表时间: 2020-03-17
• 期刊: bioRxiv : the preprint server for biology
• 作者: Lv, Huibin;Wu, Nicholas C;Mok, Chris K P
• 通讯作者: Mok, Chris K P