DEVELOPMENT OF A NONHUMAN PRIMATE MODEL FOR VARICELLA AND HERPES ZOSTER

水痘和带状疱疹非人灵长类动物模型的开发

• 批准号: 7715955
• 负责人: Ilhem Messaoudi
• 金额: $ 5.55万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715955
• 关键词: Acute; Affect; Animal Model; Animals; B-Lymphocytes; Blood; Cells; Chickenpox; Chronology; Clinical; Coculture Techniques; Computer Retrieval of Information on Scientific Projects Database; Cross-Sectional Studies; Cyclosporine; Daily; Development; Disease; Elderly; Funding; Goals; Grant; Healthcare Systems; Herpes zoster disease; Herpesvirus Type 3; Human; Immune; Immune Targeting; Immune response; Infection; Inflammation; Institution; Intervention; Kinetics; Latent Virus; Life; Lytic Virus; Modeling; Molecular; Neurons; Pain; Patients; Polymerase Chain Reaction; Population; Quality of life; Research; Research Personnel; Resources; SIV; Source; Spinal Ganglia; Time; Tissues; Transcript; United States; United States National Institutes of Health; Vaccines; Viremia; Virus; Virus Diseases; Virus Latency; base; cohort; design; experience; nonhuman primate; novel; reactivation from latency; research study; viral DNA; virus pathogenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The reactivation of latent varicella zoster virus (VZV) late in life and during immune suppression results in the painful and debilitating disease known as herpes zoster (shingles). VZV-induced neuronal destruction and inflammation during the renewed replication can cause severe pain that interferes with daily activities and reduces the quality of life for affected patients. There are an estimated one million new cases of shingles in the United States each year, which makes this disease a large epidemiological burden on the health care system. Even though several aspects of VZV infection in humans are characterized, studies on VZV pathogenesis, latency and reactivation have been severely hampered by the lack of an appropriate animal model. The identification of a closely related Simian varicella virus (SVV) offers the alternative of a nonhuman primate (NHP) model. Indeed, considerable clinical and molecular similarities between SVV and VZV indicate that SVV infection of NHP has considerable potential as an animal model. The goals of the proposed studies are two-fold: 1) To study the host immune factors that resolve the acute varicella infection in young RM; 2) To understand the host immune factors that maintain viral latency and fail during reactivation. These goals will be explored in two aims as described below. Experiments described in these aims will lay the groundwork for designing novel safer vaccines and interventions to protect the elderly and immune suppressed population from herpes zoster. Aim 1: Establish the kinetics of the primary SVV infection and the ensuing adaptive immune response. In this aim we will determine the kinetics of SVV dissemination and the subsequent adaptive immune response in various tissues in RM using a cross-sectional study. Animals will be sacrificed in a chronological manner after primary i.v. inoculation, and the levels of viral DNA as well as the presence of lytic virus will be determined in various target tissues, utilizing real-time PCR and co-culture analysis on susceptible cells. We will also characterize the duration, magnitude and kinetics of the T and B cell immune response following primary viral infection, as well as identify potential targets of immune recognition. Aim 2: Determine the chronology of SVV latency in RM dorsal root ganglia and reactivation following immune deficiency. In this aim we will determine the chronology of SVV latency in this animal species. Animals will be infected as described in Aim 1. The level of viremia in the blood will be determined on a weekly basis for the first month and biweekly thereafter. When viral DNA is not detected on 2 consecutive time points, the animals will be sacrificed and target tissues will be collected and analyzed for the presence of several SVV transcripts associated with latency. We will also investigate whether SVV could reactivate in the form of a zoster in RM. We will create a state of immune suppression in animals that harbor latent SVV. Since herpes zoster occurs frequently in patients who are experiencing severe immune suppression, we will infect a cohort of SVV-latent animals with SIV, and treat a second cohort of latently infected animals with cyclosporine A to create a state of general immune suppression.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 潜伏的水痘带状疱疹病毒（VZV）在生命后期和免疫抑制期间的重新激活导致疼痛和衰弱的疾病，称为带状疱疹（带状疱疹）。VZV在重新复制期间诱导的神经元破坏和炎症可引起严重疼痛，干扰日常活动并降低受影响患者的生活质量。据估计，美国每年有100万新的带状疱疹病例，这使得这种疾病成为卫生保健系统的一个巨大的流行病学负担。尽管人类VZV感染的几个方面的特点，VZV的发病机制，潜伏期和再激活的研究已严重阻碍了缺乏适当的动物模型。 一个密切相关的猿猴水痘病毒（SVV）的鉴定提供了一个非人灵长类动物（NHP）模型的替代。实际上，SVV和VZV之间相当大的临床和分子相似性表明NHP的SVV感染作为动物模型具有相当大的潜力。拟议研究的目标有两个方面： 1)目的：研究宿主免疫因素对水痘病毒感染的影响; 2）了解维持水痘病毒潜伏期和再激活失败的宿主免疫因素。这些目标将在下文所述的两个目标中加以探讨。这些目标中描述的实验将为设计新的更安全的疫苗和干预措施奠定基础，以保护老年人和免疫抑制人群免受带状疱疹的侵害。 目的1：建立原发性SVV感染和随后的适应性免疫应答的动力学。 在这个目标中，我们将确定SVV传播的动力学和随后的适应性免疫反应在RM的各种组织中使用的横断面研究。初次静脉接种后，将按时间顺序处死动物，并采用实时PCR和易感细胞共培养分析，测定各种靶组织中的病毒DNA水平以及是否存在裂解病毒。我们还将描述原发性病毒感染后T和B细胞免疫应答的持续时间、幅度和动力学，以及识别免疫识别的潜在靶点。 目的2：确定RM背根神经节SVV潜伏期和免疫缺陷后再激活的时间表。 为此，我们将确定该动物种属中SVV潜伏期的时间顺序。动物将按照目的1所述进行感染。第一个月每周测定一次血液中的病毒血症水平，此后每两周测定一次。当在2个连续时间点未检测到病毒DNA时，将处死动物，收集靶组织并分析是否存在与潜伏期相关的几种SVV转录物。我们还将研究SVV是否可以在RM中以带状疱疹的形式重新激活。我们将在潜伏SVV的动物中创造一种免疫抑制状态。由于带状疱疹经常发生在经历严重免疫抑制的患者中，我们将用SIV感染一组SVV潜伏动物，并用环孢菌素A治疗第二组潜伏感染动物，以产生全身免疫抑制状态。