Control of influenza virus by sphingolipid metabolism

描述（由申请人提供）：流感病毒继续威胁人类，仍然是世界各地的主要健康问题。流感病毒感染后，宿主产生I型干扰素（IFN）以抑制病毒传播。虽然I型IFN干扰病毒复制并刺激宿主免疫以保护宿主免受有害的病毒细胞毒性，但IFN本身可引起有害的炎症反应。因此，必须确定和追踪调节I型IFN的局部诱导和活性的因素，以更好地理解和操纵宿主与流感病毒之间的相互作用。 鞘脂是生物活性的脂质介质，包括1-磷酸鞘氨醇（S1 P）和神经酰胺，调节多种细胞条件，具有重要的治疗潜力。然而，鞘脂代谢调节宿主保护性信号传导和针对流感病毒感染的免疫应答的作用模式仍然未知。 初步数据表明，S1 P裂解酶的过表达使细胞对流感病毒感染和病毒致细胞病变作用具有抗性。JAK/STAT I型IFN信号的激活对于由S1 P裂解酶介导的宿主防御机制至关重要。相比之下，过表达鞘氨醇激酶（SK）1的细胞更容易受到感染，阻断SK 1的抑制剂显示出抗流感病毒活性。此外，神经酰胺类似物显著增强了流感病毒感染后树突状细胞（DC）中I型IFN的诱导，并且还增强了DC成熟和T细胞刺激。这些结果表明，鞘脂代谢的能力，以控制主机的保护和免疫的一部分，通过功能的I型干扰素。本研究将进一步探讨S1 P代谢酶和神经酰胺对流感病毒增殖和致病的调控作用。独特的研究目的和实验包括：1）确定S1 P代谢酶控制流感病毒复制的细胞内信号传导机制，2）通过使用SK 1特异性抑制剂来确定SK 1阻断在流感发病机制和宿主对感染的免疫中的作用，3）研究神经酰胺对流感病毒传播和宿主免疫应答的作用机制，特别是通过抗原呈递DC和抗病毒T细胞。最终，这里提出的研究应该产生对调节病毒复制的细胞信号的详细理解，并促进治疗病毒性疾病的治疗干预措施的发展。

DESCRIPTION (provided by applicant): Influenza virus continues to threaten humans and remains a major health concern around the world. Following influenza virus infection, the host produces type I interferon (IFN) to inhibit viral spread. Although type I IFN interferes with virus replication and stimulates host immunity to protect the host from harmful viral cytotoxicity, the IFN itself can cause a detrimental inflammatory response. Therefore, factors that regulate the local induction and activity of type I IFN must be identified and traced to better understand and manipulate the interplay between the host and the influenza virus. The sphingolipids are bioactive lipid mediators, which include sphingosine 1-phosphate (S1P) and ceramide, that regulate multiple cellular conditions with important therapeutic potential. However, the action mode by which sphingolipid metabolism modulates the host protective signaling and immune response against influenza virus infection remains unknown. Preliminary data indicate that overexpression of S1P lyase renders cells resistant to influenza virus infection and viral cytopathic effects. Activation of JAK/STAT type I IFN signaling is critical for the host defensive mechanism mediated by S1P lyase. In contrast, cells overexpressing sphingosine kinase (SK) 1 are more susceptible to the infection, and an inhibitor blocking SK1 displayed anti-influenza viral activity. Further, a ceramide analog dramatically enhanced the induction of type I IFN in dendritic cells (DCs) upon influenza virus infection and also enhanced DC maturation and T cell stimulation. These results indicate the capacity of sphingolipid metabolism to control host protection and immunity in part via the function of type I IFN. In this study, the regulation of influenza virus propagation and viral pathogenesis by S1P-metabolizing enzymes and ceramide will be further investigated. The unique research aims and experiments include 1) determining the intracellular signaling mechanism by which S1P-metabolizing enzymes control influenza virus replication, 2) defining the role of SK1 blockade in influenza pathogenesis and host immunity to the infection by using SK1- specific inhibitors, and 3) investigating the mechanism of ceramide's effect on influenza virus spread and host immune responses, specifically via antigen-presenting DCs and anti-viral T cells. Ultimately, the research proposed here should produce a detailed understanding of cellular signals that regulate viral replication and promote the development of therapeutic interventions to remedy viral diseases.