Interplay between influenza virus and S1P-metabolizing enzymes

项目摘要 流感作为对人类健康的全球性威胁，继续导致显著的发病率和高发病率。 mortality.要有效地控制流感，了解宿主与 通过识别调节病毒复制的宿主因子并确定 流感病毒操纵细胞防御或信号传导途径。鞘脂是一种具有生物活性的脂类 介质，包括鞘氨醇1-磷酸（S1 P）。虽然S1 P及其代谢酶，如 S1 P裂解酶（SPL）和鞘氨醇激酶2（SK 2）已被报道可调节多种细胞或疾病 在流感病毒感染过程中，它们的作用知之甚少。初步数据显示，SPL 促进IKKε介导的I型干扰素（IFN）应答以显示抗流感病毒活性。然而，在这方面， 流感病毒有效地下调SPL，表明流感病毒努力逃避宿主 防御机制此外，流感病毒增加了另一种S1 P代谢酶的水平， SK2，加速流感病毒复制。抑制SK2削弱流感病毒在小鼠中的繁殖 体外培养，并增加病毒感染小鼠的生存力，证明了SK2的促流感功能。这些 研究结果表明，需要进一步研究S1 P代谢酶、宿主 防御和信号传导，以及流感病毒。本建议的研究目的包括：1）确定 流感病毒操纵SPL和SK 2以增强病毒复制的机制，2）研究 这些S1 P代谢酶如何显示抗病毒或促流感病毒活性的机制，以及 3)建立流感病毒体内感染过程中S1 P代谢酶的功能。 总的来说，这些研究结果可以定义S1 P代谢酶的调节功能， 影响宿主防御和流感致病性。此外，该项目还可以为以下方面奠定基础： 设计治疗流感的新干预措施。

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.