Control of influenza virus by sphingolipid metabolism

描述(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(干扰素)以抑制病毒传播。虽然I型干扰素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，但干扰素本身可引起有害的炎症反应。因此，必须确定和追踪调节I型干扰素局部诱导和活性的因素，以更好地了解和操纵宿主和流感病毒之间的相互作用。鞘磷脂是一类具有生物活性的脂质介质，包括鞘氨醇1-磷酸(S1P)和神经酰胺，调节多种细胞状态，具有重要的治疗潜力。然而，鞘磷脂代谢调节宿主对流感病毒感染的保护信号和免疫反应的作用模式尚不清楚。初步数据表明，过表达S1P裂解酶可使细胞对流感病毒感染和病毒细胞病变产生抵抗力。JAK/STAT I型干扰素信号的激活对S1P裂解酶介导的宿主防御机制至关重要。相比之下，过度表达鞘氨醇激酶(SK)1的细胞更容易受到感染，而阻断SK1的抑制剂显示出抗流感病毒的活性。此外，神经酰胺类似物显著增强流感病毒感染后树突状细胞(DC)中I型干扰素的诱导，并促进DC成熟和T细胞刺激。这些结果表明鞘磷脂代谢在一定程度上通过I型干扰素的作用来控制宿主保护和免疫。本研究将进一步探讨S1P代谢酶和神经酰胺对流感病毒增殖和致病机制的调控作用。其独特的研究目的和实验包括：1)确定S1P代谢酶控制流感病毒复制的细胞内信号机制；2)利用SK1特异性抑制剂确定SK1阻断在流感发病和宿主免疫中的作用；3)研究神经酰胺对流感病毒传播和宿主免疫反应的影响机制，特别是通过抗原提呈树突状细胞和抗病毒T细胞。最终，这里提出的研究应该会对调节病毒复制的细胞信号产生详细的理解，并促进治疗干预措施的发展，以治疗病毒疾病。 公共卫生相关性：流感病毒是一个主要的公共卫生问题，需要识别细胞变化以抑制病毒的致病性以控制其。最近发现的鞘磷脂作为调节重要细胞过程的介质，促使我们研究了这些因素及其代谢酶在I型干扰素介导的宿主对流感病毒感染的反应中的作用。揭示这种相互作用的分子信号机制，以及鞘磷脂代谢对病毒致病性和宿主免疫应答的影响，为未来攻克病毒疾病的新疗法的开发提供了一条有希望的途径。

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. PUBLIC HEALTH RELEVANCE: Influenza virus is a major public health concern, requiring identification of cellular changes to inhibit viral pathogenicity for its control. Recent discovery of sphingolipids as mediators that modulate important cellular processes prompted us to investigate the roles of these factors and their metabolizing enzymes in the type I interferon-mediated host response to influenza virus infection. Uncovering the molecular signaling mechanisms of this interaction and the effect of sphingolipid metabolism on viral pathogenicity and the host immune response comprises a promising route for the future development of novel therapeutics to conquer viral diseases.