REGULATION OF HOST RESPONSES TO RESPIRATORY VIRAL INFECTION BY ISG15

宿主对病毒感染的反应是复杂的，并且必须平衡抑制病原体（疾病）的复制。 抗性），对宿主的损害有限（疾病耐受性）。宿主对病毒应答的关键介质 感染是I型干扰素和它们诱导的数百个干扰素刺激基因。当中分别有 泛素样蛋白ISG15作为抗病毒蛋白发挥作用，限制许多病毒的复制。我们的研究 已经证明ISG15也可以调节宿主应答和从病毒感染中恢复， 独立于对病毒复制的任何影响，这一过程被称为疾病耐受性。呼吸道病毒感染期间 我们已经检测到在缺乏ISG15的细胞和小鼠中上皮损伤增加。本提案中 我们将探索ISG15在急性病毒感染过程中保护上皮免受损伤的机制。 感染在目的1中，我们将确定ISG15是否通过调节细胞死亡、凋亡和细胞凋亡的类型来保护宿主。 vs.坏死性凋亡，在急性病毒感染期间在呼吸道上皮细胞中开始。在目标2中，我们将确定 ISG15通过与RIPK1和RIPK3的相互作用，作为分子开关来调节细胞内的蛋白质水平。 A型流感病毒感染期间坏死性凋亡和细胞凋亡诱导。通过以下方式了解机制 其中ISG15通过抑制病毒复制和通过限制宿主的免疫应答来保护宿主免受病毒感染。 对宿主诱导的损伤可能导致靶向该途径的治疗的发展， 用于治疗急性病毒感染。

The host response to viral infection is complex and must balance inhibiting replication of the pathogen (disease resistance) with limiting damage to the host (disease tolerance). A key mediator of the host response to viral infection are type I interferons and the hundreds of interferon stimulated genes they induce. Among these, the ubiquitin-like protein ISG15, functions as an antiviral protein, limiting replication of many viruses. Our studies have demonstrated that ISG15 can also regulate the host response and recovery from viral infection, independent of any effects on viral replication, a process known as disease tolerance. During respiratory viral infection we have detected increased epithelial damage in both cells and mice lacking ISG15. In this proposal we will explore the mechanism by which ISG15 protects the epithelium from damage during acute viral infection. In Aim 1 we will determine if ISG15 protects the host by regulating the type of cell death, apoptosis vs. necroptosis, initiated in respiratory epithelial cells during acute viral infection. In Aim 2 we will determine if ISG15, through its interactions with RIPK1 and RIPK3, functions as a molecular switch to regulate the induction of necroptosis and apoptosis during influenza A virus infection. Understanding the mechanism by which ISG15 protects the host from viral infection, both through inhibition of viral replication and by limiting the damage induced to the host may lead to the development of therapies that target this pathway and can be used for the treatment of acute viral infections.