Control of influenza virus by sphingolipid metabolism

通过鞘脂代谢控制流感病毒

• 批准号: 8182069
• 负责人: BUMSUK HAHM
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182069
• 关键词: Address; Affect; Animal Model; Antigens; Biochemical; Biological Assay; Biological Process; Body Weight decreased; Cell Line; Cell Maturation; Cell physiology; Cells; Ceramides; Complex; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Enzymes; Future; Genes; Goals; Health; Host Defense; Human; Immune response; Immune system; Immunity; Infection; Inflammatory Response; Influenza; Interferon Type I; Interferons; JAK1 gene; Laboratories; Link; Lung; Mediating; Mediator of activation protein; Metabolism; Molecular; Molecular Analysis; Monitor; Mus; Pathogenesis; Pathogenicity; Predisposition; Production; Public Health; Receptor Activation; Regulation; Replication-Associated Process; Research; Resistance; Resistance to infection; Role; Route; SPHK1 enzyme; STAT1 gene; Signal Pathway; Signal Transduction; Sphingolipids; Survival Rate; T cell response; T-Lymphocyte; TRAF2 gene; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Viral; Viral Cytopathogenic Effect; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Replication; analog; anti-influenza; base; cytokine; cytotoxicity; defense response; design; in vivo; influenzavirus; inhibitor/antagonist; lipid mediator; novel therapeutics; overexpression; research study; respiratory; sphingosine 1-phosphate; sphingosine-1-phosphate lyase; theories; type I interferon receptor

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.

描述（由申请人提供）：流感病毒继续威胁人类，并且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）来抑制病毒传播。尽管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局部诱导和活性的因素，以便更好地了解和操纵宿主与流感病毒之间的相互作用。鞘脂是一种生物活性脂质介质，包括鞘磷脂1-磷酸（S1P）和神经酰胺，它们调节多种细胞状况，具有重要的治疗潜力。然而，鞘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，S1P裂解酶的过表达使细胞抵抗流感病毒感染和病毒的细胞病变作用。JAK/STAT I型IFN信号的激活对于S1P裂解酶介导的宿主防御机制至关重要。相反，过度表达鞘氨醇激酶（SK） 1的细胞更容易受到感染，并且阻断SK1的抑制剂显示出抗流感病毒活性。此外，神经酰胺类似物在流感病毒感染后显著增强了树突状细胞（DC）中I型IFN的诱导，也增强了DC成熟和T细胞刺激。这些结果表明鞘脂代谢部分通过I型IFN的功能控制宿主保护和免疫的能力。本研究将进一步探讨s1p代谢酶和神经酰胺对流感病毒传播和病毒发病的调控作用。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阻断在流感发病机制和宿主免疫感染中的作用；3)研究神经酰胺对流感病毒传播和宿主免疫反应的作用机制，特别是通过抗原呈递dc和抗病毒T细胞。最终，本文提出的研究应该详细了解调节病毒复制的细胞信号，并促进治疗性干预措施的发展，以治疗病毒性疾病。