Immunoregulatory Activities of HSV gD Binding to its Entry Receptors

HSV gD 与其进入受体结合的免疫调节活性

• 批准号: 8507834
• 负责人: Claude F Krummenacher
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507834
• 关键词: Address; Adult; Affect; Afferent Neurons; American; Antigen Presentation; Antigens; Antiviral Agents; Antiviral Therapy; Binding; Binding Sites; Biological Response Modifiers; CD28 gene; CD8B1 gene; Cell Adhesion Molecules; Cell Line; Cell physiology; Cells; Characteristics; Collaborations; Complex; Data; Disease; Down-Regulation; Endocytosis; Epithelial Cells; Epithelium; Equilibrium; Event; Glycoproteins; Goals; Grant; Herpesvirus 1; Host Defense; Human; Human Herpesvirus 2; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunologist; Immunosuppression; Infection; Intervention; Investigation; Jordan; Kinetics; Lead; Learning; Life Cycle Stages; Ligands; Light; Location; Molecular; Molecular Conformation; Molecular Immunology; NK Cell Activation; Natural Immunity; Natural Killer Cells; Neurons; Oranges; PVRL1; Pathway interactions; Play; Predisposition; Production; Publishing; Recurrence; Reporting; Role; Simplexvirus; Site; Specificity; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Translating; Tumor Necrosis Factor Receptor; Vaccines; Viral; Virus; Virus Diseases; Virus Receptors; arm; base; cytotoxic; cytotoxicity; design; glycoprotein structure; herpesvirus entry mediator; immunological synapse; in vivo; novel; novel therapeutics; pathogen; prevent; receptor; receptor binding; response; tool; transmission process

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is a common human pathogen causing lifelong infection. HSV infects and replicates in epithelial cells before spreading to sensory neurons where it establishes a lifelong latency punctuated by frequent reactivation events. Cytotoxic cells of the innate and adaptive immune systems play critical roles in limiting primary and recurrent viral spread and replication in epithelia. Furthermore, cytotoxic CD8+ T cells control the extent of viral reactivation from latently infected neurons. My goal is t learn how HSV affects the function of cytotoxic cells by altering key immunoregulatory functions of its two main entry receptors: HVEM and nectin-1. It is remarkable that both receptors are also involved in complex networks of interactions that balance the activation and inhibition of cytolyti cells. HVEM is at the crossroad between TNFR and CD28 co-modulatory networks of T cells during antigen recognition. Nectin-1 is a ligand for the NK cell activating receptor CD96 but its role in innate immunity remains relatively unclear. I showed that binding of the viral ligand, HSV gD, can affect the function of HVEM and nectin-1 in two ways: by competing with natural ligands and by inducing receptor endocytosis. Thus, my general hypothesis is that HSV uses gD as a non-canonical ligand to alter the host's defenses. In this grant I will compare and contrast how gD affects the function of CTL and NK cells towards infected cells. The proposed aims will focus on molecular interactions (aim 1), target recognition (aim 2), and functional activation (aim 3). Aim 1 is based on my preliminary data that compare the structures of HVEM and nectin-1 bound to gD or to their respective natural ligands. The gD binding sites overlap but differ from the functional sites of the receptors suggesting that gD can compete with natural ligands and induce a specific response. In Aim 2, I will study how gD perturbs the contacts between cytolytic cells and their targets by affecting nectin-1 and HVEM at the NK and CTL immunological synapses respectively. To address NK and T cell function in Aim 3, I established collaborations with Drs J. Orange and J. Riley (both at PENN) and Dr D. Nardelli Haefliger (U. of Lausanne). I will investigate how gD affects the activation of NK cells and modulates CD8 T cell cytotoxicity in the presence or absence of antigen presentation. Successful completion of this study will define how gD, a key entry glycoprotein functions in two novel immune evasion strategies for HSV by targeting key regulators of the innate and adaptive immune responses. I have proposed testable hypotheses to understand the immunological role of gD during HSV infection and to use it as a tool to unravel the complex immunoregulatory networks involved in cytolytic activity of NK and T cells in general. This "molecular immunology" approach will open possibilities to address these functions in vivo. Furthermore, data from this study may suggest ways to design novel antiviral interventions.

描述（由申请人提供）： 单纯疱疹病毒（HSV）是一种常见的人类病原体，可导致终身感染。 HSV 在传播到感觉神经元之前会在上皮细胞中感染并复制，并在感觉神经元中建立终生潜伏期，期间会出现频繁的重新激活事件。先天性和适应性免疫系统的细胞毒性细胞在限制上皮细胞中原发性和复发性病毒传播和复制方面发挥着关键作用。此外，细胞毒性 CD8+ T 细胞控制潜伏感染神经元病毒再激活的程度。 我的目标是了解 HSV 如何通过改变其两个主要进入受体（HVEM 和 nectin-1）的关键免疫调节功能来影响细胞毒性细胞的功能。值得注意的是，这两种受体还参与平衡溶细胞细胞的激活和抑制的复杂相互作用网络。在抗原识别过程中，HVEM 处于 T 细胞 TNFR 和 CD28 共调节网络的十字路口。 Nectin-1 是 NK 细胞激活受体 CD96 的配体，但其在先天免疫中的作用仍相对不清楚。我发现病毒配体 HSV gD 的结合可以通过两种方式影响 HVEM 和 nectin-1 的功能：与天然配体竞争和诱导受体内吞作用。因此，我的一般假设是 HSV 使用 gD 作为非规范配体来改变宿主的防御。在这笔资助中，我将比较和对比 gD 如何影响 CTL 和 NK 细胞对感染细胞的功能。拟议的目标将集中于分子相互作用（目标 1）、目标识别（目标 2）和功能激活（目标 3）。 目标 1 基于我的初步数据，该数据比较了 HVEM 和 nectin-1 与 gD 或其各自天然配体结合的结构。 gD 结合位点与受体的功能位点重叠但不同，表明 gD 可以与天然配体竞争并诱导特异性反应。在目标 2 中，我将研究 gD 如何通过分别影响 NK 和 CTL 免疫突触处的 nectin-1 和 HVEM 来扰乱溶细胞细胞与其靶标之间的接触。为了解决目标 3 中的 NK 和 T 细胞功能问题，我与 J. Orange 博士和 J. Riley 博士（均来自 PENN）以及 D. Nardelli Haefliger 博士（洛桑大学）建立了合作关系。我将研究 gD 如何影响 NK 细胞的激活并在存在或不存在抗原呈递的情况下调节 CD8 T 细胞的细胞毒性。 这项研究的成功完成将明确 gD（一种关键的进入糖蛋白）如何通过针对先天性和适应性免疫反应的关键调节因子，在两种新型 HSV 免疫逃避策略中发挥作用。我提出了可检验的假设，以了解 gD 在 HSV 感染期间的免疫学作用，并将其用作解开涉及 NK 和 T 细胞溶细胞活性的复杂免疫调节网络的工具。这种“分子免疫学”方法将为在体内解决这些功能提供可能性。此外，这项研究的数据可能会提出设计新型抗病毒干预措施的方法。

项目成果

The effect of cellular differentiation on HSV-1 infection of oligodendrocytic cells.

• DOI: 10.1371/journal.pone.0089141
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bello-Morales R;Crespillo AJ;García B;Dorado LÁ;Martín B;Tabarés E;Krummenacher C;de Castro F;López-Guerrero JA
• 通讯作者: López-Guerrero JA