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

• 批准号: 10701133
• 负责人: Yohannes Afework Mebratu
• 金额: $ 15.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701133
• 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

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.

流感病毒（IAV）负责导致严重呼吸系统疾病和死亡的季节性发作 全球，仅在美国就耗资数十亿美元。癌症患者的风险增加 在影响力之后发展次要肺炎，这可能导致重大并发症。 由于缺乏有效的治疗干预，经常出现，感染构成了严重的挑战 病毒的新菌株以及耐药性的快速发展。控制感染的新方法可能 源自直接或间接与病毒蛋白相互作用的细胞因子或途径，以增强或抑制 病毒复制。 IAV领域的新兴概念之一是宿主细胞因子和途径是 维持IAV基因组完整性所必需的，这对于病毒复制至关重要。我们的初步数据显示 宿主细胞蛋白BIK的缺乏与IAV复制的显着降低有关。我们的 主要发现发现，BIK缺乏降低了感染气道的病毒蛋白水平和病毒复制 上皮细胞。此外，与Bik+/+小鼠相比，BIK - / - 暴露于严重的肺部注射较少，肺部减少 病毒载量，并在感染IAV后的存活率显着增加。同样，单个核苷酸 Bik基因中的多态性（SNP）（G→A）增加了BIK表达水平，可显着增加病毒NP 原发性人支气管上皮细胞（NHBE）中的水平和复制。此外，来自IAV-的数据 感染的人类队列表明，BIK SNP的AA变体是与影响力疾病有关的风险等位基因 严重程度。 BIK破坏了Bcl-2与IAV编码的核蛋白（NP）的相互作用，并形成BIK/NP复合物 这可能有助于组装病毒蛋白。该建议的目标是定义宿主细胞蛋白BIK的作用 促进病毒复制。我们的中心假设是IAV增加了宿主细胞BIK蛋白的表达，这 与Bcl-2/np相互作用的相互作用并破坏允许NP组装病毒色素蛋白的成分 （VRNP）并促进有效的病毒复制。为了检验这一假设，我们提出了两个具体目标。目标1 识别IAV复制所需的病毒NP的BIK结合域。 AIM 2确定是否是 BIK SNP与BIK表达增加有关是影响力疾病严重程度的危险因素 人类。研究旨在识别BIK/NP相互作用的位点，该相互作用可能是潜在的药物靶标 将来。这项研究可能会识别有助于影响力敏感性的潜在宿主遗传危险因素 和严重性，并且可能对针对性的预防和治疗具有潜在影响 易感因素。 拟议的研究将通过解剖促进IAV的关键机制对现场产生重大影响 复制。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 通过减少IAV复制来治疗。此外，这项研究将确定导致IAV疾病的遗传因素 严重性，这可能具有广泛的公共健康意义。