The role of Bik in the replication and severity of influenza A virus

Bik 在甲型流感病毒复制和严重程度中的作用

基本信息

批准号：
10322448
负责人：
Yohannes Afework Mebratu
金额：
$ 29.19万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-08-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322448
关键词：
Affect Antiviral Agents Appearance BCL2 gene BIK gene Binding CRISPR/Cas technology Cancer Patient Cell physiology Cells Cessation of life Clinical Data Complex Data Disease Disease Management Disease Progression Dose Drug Targeting Drug resistance Epidemic Epithelial Cells Exhibits Foundations Frequencies Future GTP-Binding Protein alpha Subunits, Gs Genetic Genetic Polymorphism Goals Human Impairment Infection Infection Control Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Integration Host Factors Lead Life Link Lung Mediating Modeling Mus Mutation Nucleoproteins Pathway interactions Peptides Persons Pneumonia Predisposition Prevention Process Protein Binding Domain Protein Deficiency Proteins Public Health Pulmonary Inflammation Pulmonary Pathology Respiratory Disease Ribonucleoproteins Risk Risk Factors Role Severities Severity of illness Single Nucleotide Polymorphism Site Survival Rate Testing Therapeutic Therapeutic Intervention Time Vaccination Variant Viral Viral Drug Resistance Viral Genome Viral Load result Viral Proteins Virus Virus Diseases Virus Replication Wild Type Mouse airway epithelium base bronchial epithelium cohort cost design drug development economic cost flu genetic risk factor genome integrity human disease improved in vivo individualized prevention influenza A virus nucleoprotein influenza infection inhibitor mutant new therapeutic target novel novel strategies personalized medicine protein expression recombinant virus respiratory risk variant small molecule stem therapeutically effective

项目摘要

Influenza A virus (IAV) is responsible for seasonal epidemics that results in severe respiratory illness and deaths worldwide, costing billions of dollars annually in the U.S. alone. Cancer patients are at increased risk of developing a secondary pneumonia after influenza, which can lead to significant complications. Influenza infections pose serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus, and rapid development of drug resistance. New approaches to control infection may stem from cellular factors or pathways that directly or indirectly interact with viral proteins to enhance or inhibit virus replication. One of the emerging concepts in the field of IAV is that host cellular factors and pathways are required for maintaining IAV genome integrity, which is essential for viral replication. Our preliminary data show that a deficiency of a host cellular protein, Bik, is associated with significant reduction in IAV replication. Our major findings found that Bik deficiency reduces viral protein levels and viral replication in infected airway epithelial cells. Furthermore, bik-/- compared to bik+/+ mice exhibit less severe lung inflammation, reduced lung viral load, and a significant increase in survival rate after infection with IAV. Similarly, a single nucleotide polymorphism (SNP) in the BIK gene (G→A) that increases Bik expression levels significantly increases viral NP level and replication in primary normal human bronchial epithelial cells (NHBEs). Furthermore, data from an IAV- infected human cohort showed that the AA variant of BIK SNP is a risk allele associated with influenza disease severity. Bik disrupts the interaction of Bcl-2 with IAV-encoded nucleoprotein (NP) and form a Bik/NP complex that may help assemble viral proteins. The goals of this proposal are to define the role of a host cell protein Bik in promoting viral replication. Our central hypothesis is that IAV increases host cell Bik protein expression, which interacts with and disrupts Bcl-2/NP interaction to allow NP to assemble components of viral ribonucleoprotein (vRNP) and facilitate efficient viral replication. To test this hypothesis, we propose two Specific Aims. Aim 1 identifies the Bik-binding domain of viral NP required for IAV replication. Aim 2 determines whether a BIK SNP associated with increased Bik expression is a risk factor for influenza disease severity in humans. Studies are designed to identify the sites of Bik/NP interaction that may serve as potential drug targets in the future. This study may identify underlying host genetic risk factors contributing to influenza susceptibility and severity and may have potential implications in regard to targeted prevention and treatment based on susceptibility factors. The proposed studies will have significant impacts on the field by dissecting key mechanisms that promote IAV replication. In the long term, developing peptides or small molecules that disrupt Bik/NP interactions may improve therapy by reducing IAV replication. Further, this study will identify genetic factors contributing to IAV disease severity, which can have a broad public health significance.

甲型流感病毒 (IAV) 是导致严重呼吸道疾病和死亡的季节性流行病的原因在全球范围内，仅在美国，癌症患者每年就要花费数十亿美元。流感后出现继发性肺炎，可能导致严重的并发症。由于缺乏有效的治疗干预措施、频繁出现的感染带来了严峻的挑战新病毒株的出现以及耐药性的迅速发展可能会导致控制感染的新方法。源于直接或间接与病毒蛋白相互作用以增强或抑制的细胞因子或途径 IAV 领域的新兴概念之一是宿主细胞因子和途径。维持 IAV 基因组完整性是必需的，这对于病毒复制至关重要。宿主细胞蛋白 Bik 的缺乏与 IAV 复制的显着减少有关。主要发现发现 Bik 缺乏会降低受感染气道中的病毒蛋白水平和病毒复制此外，与 bik+/+ 小鼠相比，bik-/- 小鼠表现出较不严重的肺部炎症，肺部炎症减少。病毒载量，以及感染 IAV 后存活率显着增加。 BIK 基因 (G→A) 中的多态性 (SNP) 增加 Bik 表达水平，显着增加病毒 NP 原代正常人支气管上皮细胞（NHBE）中的水平和复制此外，数据来自 IAV-。受感染的人类队列表明 BIK SNP 的 AA 变体是与流感疾病相关的风险等位基因 Bik 会破坏 Bcl-2 与 IAV 编码的核蛋白 (NP) 的相互作用并形成 Bik/NP 复合物。该提案的目标是确定宿主细胞蛋白 Bik 的作用。我们的中心假设是 IAV 增加宿主细胞 Bik 蛋白的表达，从而促进病毒复制。与 Bcl-2/NP 相互作用并破坏其相互作用，使 NP 能够组装病毒核糖核蛋白的成分 (vRNP) 并促进有效的病毒复制，我们提出了两个具体目标 1。识别 IAV 复制所需的病毒 NP 的 Bik 结合域，目的 2 确定是否与 Bik 表达增加相关的 BIK SNP 是流感疾病严重程度的危险因素研究旨在确定可作为潜在药物靶标的 Bik/NP 相互作用位点。未来，这项研究可能会确定导致流感易感性的潜在宿主遗传风险因素。和严重程度，可能对基于此的有针对性的预防和治疗产生潜在影响易感因素。拟议的研究将通过剖析促进 IAV 的关键机制对该领域产生重大影响从长远来看，开发破坏 Bik/NP 相互作用的肽或小分子可能会改善复制。此外，这项研究将确定导致 IAV 疾病的遗传因素。严重程度，可能具有广泛的公共卫生意义。