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

说明(申请人提供)：流感病毒在禽类和人类宿主中传播，每年都会暴发，导致严重的发病率、死亡率和全球大流行的持续威胁。这种病毒的进化成功在很大程度上归功于它逃避宿主免疫的能力。病毒的致病性本身被认为是由于细胞对感染的强烈反应而导致的，这种反应因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和病原体之间的相互作用。最近，一种名为ikk？的IKK相关蛋白？被确定为细胞对流感病毒反应的一种新的分子决定因素。缺乏这种激酶的小鼠不能抑制病毒复制，因此对感染过敏。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。本提案侧重于三个相互关联的目标，以更好地描述IKK的作用？以及流感病毒诱导的致病性。目标1的重点是确定与IKK有关的激酶？流感诱导的细胞因子信号转导后的激活。目的2阐明IKK？介导的STAT1磷酸化的功能。目标3是描述IKK的水平如何？调节流感病毒感染后的细胞转录组。因此，这项建议旨在进一步阐明流感病毒感染的细胞反应，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成分。公共卫生相关性：鉴于流感病毒一直存在的全球负担，对宿主-病毒相互作用的研究可以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，诱导细胞反应，这在控制流感病毒复制方面是至关重要的。这一应用的重点是了解IKK？介导的抗病毒信号，以确定免疫调节和治疗流感病毒发病机制的新靶点。

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.