Interplay between influenza virus and S1P-metabolizing enzymes

项目摘要 流感作为对人类健康的全球威胁，继续造成严重的发病率和高发病率。 死亡率。要有效地控制流感，重要的是要了解宿主和 通过确定调节病毒复制的宿主因素和定义 流感病毒操纵细胞防御或信号通路。鞘脂是一种生物活性脂类。 介质，包括鞘氨醇1-磷酸(S1P)。虽然S1P及其代谢酶，如 S1P裂解酶(SPL)和鞘氨醇激酶2(SK2)被报道调节多种细胞或疾病 这些过程在流感病毒感染中的作用还知之甚少。初步数据表明，SPL 促进IKKε介导的I型干扰素反应以显示抗流感病毒活性。然而， 流感病毒有效下调SPL，表明流感病毒努力逃避宿主 防御机制。此外，流感病毒还增加了另一种S1P代谢酶的水平， SK2，加速了流感病毒的复制。SK2抑制流感病毒增殖的实验研究 并提高了病毒感染小鼠的存活率，证明了SK2的亲流感作用。这些 这些发现增强了进一步研究S1P代谢酶、宿主之间相互作用的必要性 防御和信号，以及流感病毒。本方案的研究目的包括：1)确定 流感病毒操纵SP1和SK2促进病毒复制的机制，2)调查 这些S1P代谢酶如何显示抗病毒或亲流感病毒活性的机制，以及 3)确定S1P代谢酶在流感病毒体内感染过程中的作用。 总的来说，这些研究结果可以定义S1P代谢酶的调节功能， 影响宿主防御和流感致病性。此外，该项目可以为 设计新的治疗措施来治愈流感。

Project Summary Influenza, as a global threat to human health, continues to cause significant morbidity and high rates of mortality. To effectively control influenza, it is important to understand the interplay between the host and influenza by identifying host factors that regulate viral replication and defining the mechanisms by which influenza virus manipulates the cellular defense or signaling pathway. Sphingolipids are bioactive lipid mediators and include sphingosine 1-phosphate (S1P). Although S1P and its metabolizing enzymes, such as S1P lyase (SPL) and sphingosine kinase 2 (SK2), have been reported to regulate versatile cellular or disease processes, their roles in influenza virus infection are poorly understood. Preliminary data indicate that SPL promoted IKKε-mediated type I interferon (IFN) responses to display anti-influenza viral activity. However, influenza viruses effectively downregulated SPL, suggesting that influenza virus strives to evade the host defense mechanism. Furthermore, influenza virus increased the level of another S1P-metabolizing enzyme, SK2, which accelerated influenza virus replication. Inhibition of SK2 impaired influenza virus propagation in vitro and increased the viability of virus-infected mice, demonstrating the pro-influenza function of SK2. These findings heighten the need to further investigate the interplay between the S1P-metabolizing enzymes, host defense and signaling, and influenza virus. The research aims of this proposal include 1) determining the mechanisms by which influenza virus manipulates SPL and SK2 to enhance virus replication, 2) investigating the mechanisms of how these S1P-metabolizing enzymes display antiviral or pro-influenza viral activities, and 3) establishing the functions of the S1P-metabolizing enzymes during influenza virus infection in vivo. Collectively, these research results can define the regulatory functions of S1P-metabolizing enzymes that impact host defenses and influenza pathogenicity. Furthermore, the project could provide a foundation for designing new therapeutic interventions to cure influenza.