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

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，仅在美国每年就花费数十亿美元。癌症患者患癌症的风险增加 在流感后发展为继发性肺炎，可能导致严重的并发症。流感 感染构成严重挑战，因为缺乏有效的治疗干预措施，频繁出现 新病毒株的出现，以及抗药性的迅速发展。控制感染的新方法可能 来源于直接或间接与病毒蛋白相互作用以增强或抑制病毒蛋白的细胞因子或途径 病毒复制。IAV领域的一个新兴概念是宿主细胞因子和途径是 这是维持IAV基因组完整性所必需的，而基因组完整性对病毒复制至关重要。我们的初步数据显示 宿主细胞蛋白BIK的缺乏与IAV复制的显著减少有关。我们的 主要研究结果发现，Bik缺乏会降低感染呼吸道中的病毒蛋白水平和病毒复制 上皮细胞。此外，与bik-/-相比，bik-/-小鼠表现出较轻的肺部炎症，减少了肺。 病毒载量，感染IAV后存活率显著提高。类似地，单核苷酸 BIk基因(G→A)的单核苷酸多态(SNP)增加了bik的表达水平，显著增加了病毒NP 原代正常人支气管上皮细胞(NHBE)的水平和复制。此外，来自IAV的数据- 感染人群队列研究表明，BIK SNP的AA变异是与流感疾病相关的危险等位基因 严肃性。Bik破坏Bcl2与IAV编码的核蛋白(NP)的相互作用，形成Bik/NP复合体 这可能有助于组装病毒蛋白质。这项提案的目标是定义宿主细胞蛋白Bik的作用 在促进病毒复制方面。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相互作用并破坏其相互作用，使NP能够组装病毒核糖核蛋白的组成部分 (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。目标2确定一个 与Bik表达增加相关的Bik SNP是中国人流感疾病严重程度的危险因素 人类。研究旨在确定可能作为潜在药物靶点的Bik/NP相互作用部位 在未来。这项研究可能确定导致流感易感性的潜在宿主遗传风险因素。 和严重性，并可能对基于以下方面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的关键机制而对该领域产生重大影响 复制。从长远来看，开发破坏Bik/NP相互作用的多肽或小分子可能会有所改善 通过减少IAV复制进行治疗。此外，这项研究将确定与IAV疾病有关的遗传因素。 严重性，这可能具有广泛的公共卫生意义。

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.