TAM Receptors and Flavivirus Infection

TAM 受体和黄病毒感染

• 批准号: 8703003
• 负责人: Greg E Lemke
• 金额: $ 39.81万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703003
• 关键词: Acute; Arboviruses; Attenuated; Binding; Biochemical; Biological; Cell Surface Receptors; Cell surface; Cells; Chemosensitization; Dendritic Cells; Dengue Virus; Disease; Encephalitis; Event; Family; Flavivirus; Flavivirus Infections; Genes; Genetic; Histologic; Human; Image; Immune response; Immune system; In Vitro; Infection; Inflammatory Response; Interferon Receptor; Interferon Type I; Interferons; Label; Ligand Binding; Ligands; Link; Measures; Mediating; Memory B-Lymphocyte; Methods; Molecular; Monoclonal Antibodies; Mus; Mutant Strains Mice; Mutation; Neuraxis; Neurons; Pathogenesis; Pathway interactions; Phosphatidylserines; Phospholipids; Physiological; Play; Production; Protein S; Protein Tyrosine Kinase; Public Health; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Relative (related person); Resistance; Role; Sentinel; Signal Transduction; Surface; T cell response; Time; Tissues; Viral; Virion; Virulent; Virus; Virus Diseases; Virus Replication; West Nile virus; chemokine; cytokine; design; in vivo; inhibitor/antagonist; macrophage; member; nervous system development; novel; particle; pathogen; receptor; research study; response; subcutaneous; type I interferon receptor; virus pathogenesis

DESCRIPTION (provided by applicant): The receptor tyrosine kinases (RTKs) of the TAM family - Tyro3, Axl, and Mer - are exploited by flaviviruses, such as West Nile Virus and Dengue Virus, to infect their target cells. The experiments of this proposal are designed to elucidate how TAM potentiation of infection is achieved. TAM RTKs are expressed on the surface of many cells, including dendritic cells and macrophages of the immune system, and neurons of the central nervous system. The ligands that bind to and activate the TAMs - Gas6 and Protein S (ProS) - have the ability to attach both to the phospholipid phosphatidylserine, expressed on the surface of flavivirus particles, and also to their cognate TAM receptor. In this way, the TAM ligands serve as a 'bridge' that links flaviviruses to the surface of cells that they will infect. t the same time, TAM receptor activation by Gas6 or ProS results in the inhibition of type I interferon (IFN) signaling, to which flaviviruses and many other viruses are sensitive. In Aim 1, genetic, biochemical, and cell biological methods will be used to dissect the mechanisms through which TAM receptors facilitate flavivirus entry into human cells in vitro. In Aim 2, these same methods will be used in experiments in dendritic cells and macrophages prepared from mice that carry targeted mutations in the Axl and Mer genes, and in CNS neurons prepared Tyro3 mutant mice, to define the TAM receptors and ligands that promote infection in different cellular settings, and to determine the extent to which TAM facilitation of flavivirus infection is dependent on the inhibition of type I IFN signaling. In Aim 3, mice that carry mutations in the Tyro3, Axl, Mer, Gas6, and ProS genes will be used to assess the cellular and immunological consequences of specific deficits in TAM signaling for infection by West Nile Virus in vivo. Together, these experiments will delineate the molecular, cellular, and physiological features of a heretofore unknown pathway of flavivirus infection.

描述（由申请人提供）：TAM 家族的受体酪氨酸激酶 (RTK) - Tyro3、Axl 和 Mer - 被黄病毒（例如西尼罗病毒和登革热病毒）利用来感染其靶细胞。该提案的实验旨在阐明如何 实现了 TAM 感染增强。 TAM RTK 在许多细胞的表面表达，包括免疫系统的树突状细胞和巨噬细胞以及中枢神经系统的神经元。结合并激活 TAM 的配体 - Gas6 和 Protein S (ProS) - 能够附着在黄病毒颗粒表面表达的磷脂磷脂酰丝氨酸上，也能够附着在其同源 TAM 受体上。通过这种方式，TAM 配体充当了一座“桥梁”，将黄病毒与它们将感染的细胞表面连接起来。同时，Gas6 或 ProS 激活 TAM 受体会抑制黄病毒和许多其他病毒对此敏感的 I 型干扰素 (IFN) 信号传导。在目标 1 中，将使用遗传、生化和细胞生物学方法来剖析 TAM 受体促进黄病毒在体外进入人体细胞的机制。在目标 2 中，这些相同的方法将用于实验中，在由携带 Axl 和 Mer 基因靶向突变的小鼠制备的树突状细胞和巨噬细胞中，以及在中枢神经系统神经元中制备的 Tyro3 突变小鼠中，以定义促进感染的 TAM 受体和配体在不同的细胞环境中，并确定 TAM 促进黄病毒感染在多大程度上依赖于 I 型 IFN 信号传导的抑制。在目标 3 中，携带 Tyro3、Axl、Mer、Gas6 和 ProS 基因突变的小鼠将用于评估体内西尼罗河病毒感染的 TAM 信号传导特定缺陷的细胞和免疫学后果。这些实验将共同描述迄今为止未知的黄病毒感染途径的分子、细胞和生理特征。