Modulation of the host response to influenza virus infection: The IKKe Kinase

描述（由申请方提供）：流感病毒在禽类和人类宿主中传播，每年爆发，导致严重的发病率、死亡率和全球大流行的持续威胁。病毒进化的成功主要归功于其逃避宿主免疫的能力。病毒致病性本身被认为是由对感染的强烈细胞应答引起的，所述细胞应答由于病毒特异性拮抗蛋白的表达而变得无效。因此，未来抗病毒药物和疫苗设计的成功需要彻底了解这些宿主-病原体相互作用。最近，IKK相关激酶IKK？被鉴定为流感病毒细胞应答中的一种新的分子决定簇。缺乏这种激酶的小鼠不能抑制病毒复制，因此对感染高度敏感。这些数据表明，这种激酶及其控制的细胞途径是令人兴奋的新的候选抗病毒靶点。这项建议的重点是三个相互关联的目标，以更好地描述IKK的作用？和流感病毒诱导的致病性。目的1的重点是确定负责IKK？流感诱导的细胞因子信号传导后的激活。目的二是阐明IKK？介导的STAT 1磷酸化。目的3是表征IKK水平如何？调节流感病毒感染后的细胞转录组。因此，该建议旨在进一步阐明细胞对流感病毒感染的反应，以确定病毒致病性的决定因素，并发现用于抗病毒药物和疫苗设计的新组分。公共卫生相关性：鉴于流感病毒的全球负担一直存在，宿主-病毒相互作用的研究可能会导致对人类健康产生直接影响的发现。我们发现IKK？，一种病毒和干扰素激活的激酶，诱导在控制流感病毒复制中至关重要的细胞应答。此应用程序的重点是了解IKK？-介导的抗病毒信号传导，以鉴定用于免疫调节和治疗流感病毒发病机制的新靶标。

DESCRIPTION (provided by applicant): Influenza viruses circulate in both avian and human hosts and account for annual outbreaks resulting in significant morbidity, mortality and the constant threat of a worldwide pandemic. The viruses' evolutionary success is largely credited to its capacity for evading host immunity. Viral pathogenicity itself is thought to result from the robust cellular response to infection that is rendered ineffective by the expression of virus- specific antagonistic proteins. Therefore, the success of future antiviral drug and vaccine design demands a thorough understanding of these host-pathogen interactions. Recently, an IKK-related kinase called IKK? was identified as a novel molecular determinant in the cellular response to influenza virus. Mice lacking this kinase were unable to inhibit virus replication and were thus rendered hypersusceptible to infection. These data suggest that this kinase, and the cellular pathway which it controls, serve as exciting new candidate antiviral targets. This proposal focuses on three interrelated aims to better characterize the role of IKK? and influenza virus-induced pathogenicity. The focus of Aim 1 is to identify the kinase responsible for IKK? activation following influenza-induced cytokine signaling. Aim 2 is to elucidate the function of IKK?-mediated phosphorylation of STAT1. Aim 3 is to characterize how the levels of IKK? modulate the cellular transcriptome following influenza virus infection. This proposal is thus designed to further elucidate the cellular response to influenza virus infection, to identify determinants of viral pathogenicity, and to discover novel components for use in antiviral drug and vaccine design. PUBLIC HEALTH RELEVANCE: Given the ever-present global burden of influenza virus, the study of host-virus interactions can result in discoveries that have immediate impact on human health. We have discovered that IKK?, a virus- and interferon-activated kinase, induces a cellular response that is critical in controlling influenza virus replication. This application focuses on understanding IKK?-mediated anti-viral signaling in order to identify novel targets for immune modulation and the treatment of influenza virus pathogenesis.