Molecular Biology Of Varicella Zoster Virus Infection

水痘带状疱疹病毒感染的分子生物学

• 批准号: 10692020
• 负责人: Jeffrey Cohen
• 金额: $ 19.94万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692020
• 关键词: Adjuvant; Adult; Advisory Committees; Affect; Agammaglobulinaemia tyrosine kinase; Antibody Response; Attenuated; Axon; B-Lymphocytes; Cell Adhesion Molecules; Cell Line; Cells; Chickenpox; Chickenpox Vaccine; Chronic Lymphocytic Leukemia; Cranial Nerves; Disease; Ectopic Expression; Ganglia; Gene Expression Profiling; Glycoproteins; Goals; Herpes zoster disease; Herpesvirus Type 3; Human; Immunization; Immunocompetent; Immunocompromised Host; Infection; Lead; Mammalian Cell; Mediating; Mediator of activation protein; Modeling; Molecular Biology; Morbidity - disease rate; Neurons; PVRL1; Pathogenesis; Patients; Persons; Predisposition; Prevention; Preventive measure; Primary Infection; Recombinants; Resistance; Signal Pathway; Tyrosine Kinase Inhibitor; United States; United States Food and Drug Administration; Vaccines; Virus; Virus Diseases; Zoster Vaccine; afferent nerve; aged; base; human stem cells; improved; knock-down; mortality

Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. At present, one zoster vaccine is licensed and available for use in the United States. The recombinant zoster vaccine (RZV) consists of recombinant VZV glycoprotein E formulated in AS01B adjuvant. RZV was approved by the Food and Drug Administration for the prevention of herpes zoster in adults aged 50 years and in October 2017 the Advisory Committee on Immunization Practices recommended RZV for use in immunocompetent adults aged 50 years. At present, it is unknown if patients with chronic lymphocytic leukemia (CLL) who have never been treated for their disease or who are receiving Bruton tyrosine kinase inhibitors, which interfere with B cell signaling pathways and may affect antibody responses, can respond well to RZV or other vaccines. In FY 2022 we used a human stem cell-based neuronal model to characterize cellular factors that mediate entry of VZV into cells. Through transcriptional profiling of infected cells, we identified the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of nectin-1 in the cell or incubation of cells with soluble forms of nectin-1 produced in mammalian cells resulted in a marked decrease in VZV infectivity of neurons. While addition of soluble nectin-1 during viral infection inhibited infectivity, addition after infection had no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection conferred susceptibility to VZV infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.

水痘带状疱疹病毒（VZV）在原发性感染期间建立了人类感觉和颅神经神经节的潜伏期，并且该病毒可以重新激活并引起初次感染后的带状疱疹。目前，一种带轮疫苗已获得许可并在美国使用。 重组带状疱疹疫苗（RZV）由AS01B佐剂中配制的重组VZV糖蛋白E组成。 RZV获得了50岁成年人预防疱疹带状疱疹的食品和药物管理局的批准，2017年10月，免疫实践咨询委员会建议RZV用于50岁以上的免疫能力成年人。 目前，尚不清楚慢性淋巴细胞性白血病（CLL）是否从未接受过疾病治疗或接受Bruton酪氨酸激酶抑制剂，这些患者会干扰B细胞信号途径并可能影响抗体反应，可能会对RZV或其他疫苗反应良好。 在2022财年，我们使用了人类干细胞的神经元模型来表征介导VZV进入细胞的细胞因子。通过对感染细胞的转录分析，我们将细胞粘附分子nectin-1鉴定为VZV进入的候选介质。 Nectin-1在神经元的细胞体和轴突中高度表达。在细胞中敲低nectin-1，或用哺乳动物细胞中产生的蜜位蛋白1的可溶性形式孵育导致神经元VZV感染性的明显降低。虽然在病毒感染期间添加可溶性奈克蛋白1抑制感染性，但感染后的添加对感染性没有影响。人Nectin-1在对生产性VZV感染具有抗VZV感染的易感性的细胞系中的异位表达。总之，我们已经将Nectin-1确定为VZV的神经元进入介质。将Nectin-1鉴定为神经元VZV进入介体可能会导致改进的治疗方法和预防措施，以降低VZV相关的发病率和死亡率。