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

IKKe激酶对流感病毒感染宿主应答的调节 项目摘要 流感病毒在禽类和人类宿主中传播，每年爆发， 严重的发病率、死亡率和全球流行病的持续威胁。病毒的进化 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反应引起的，这种反应由于病毒的表达而变得无效， 特异性拮抗蛋白因此，未来抗病毒药物和疫苗设计的成功需要一个 彻底了解这些宿主-病原体相互作用。最近，IKK相关激酶IKKe被 在细胞对流感病毒的反应中被鉴定为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 这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药物， 目标的该建议侧重于三个相互关联的目标，以更好地描述IKKe和流感的作用 病毒诱导的致病性。目标1的重点是确定负责IKKe激活的激酶 流感诱导的细胞因子信号传导。目的二是阐明IKKE介导的细胞凋亡的功能 STAT 1的磷酸化。目的3是表征IKKe水平如何调节细胞转录组 流感病毒感染后。因此，该提议旨在进一步阐明细胞对 流感病毒感染，以确定病毒致病性的决定因素，并发现新的成分， 用于抗病毒药物和疫苗设计。

Modulation of the host response to influenza virus infection: The IKKe Kinase Project Summary 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 IKKe 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 IKKe and influenza virus-induced pathogenicity. The focus of Aim 1 is to identify the kinase responsible for IKKe activation following influenza-induced cytokine signaling. Aim 2 is to elucidate the function of IKKe-mediated phosphorylation of STAT1. Aim 3 is to characterize how the levels of IKKe 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.