Impact of immune senescence on herpes zoster in a nonhuman primate model

免疫衰老对非人灵长类动物模型中带状疱疹的影响

• 批准号: 8235846
• 负责人: Ilhem Messaoudi
• 金额: $ 30.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235846
• 关键词: Acute; Affect; Age; Aging; American; Animal Model; Animals; Antibody Formation; Appearance; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cellular Immunity; Chickenpox; Clinical; Clinical Research; Coupled; Data; Defect; Development; Disease; Elderly; Equilibrium; Exanthema; Frequencies; Generations; Health; Herpes zoster disease; Herpesvirus Type 3; Homologous Gene; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Incidence; Individual; Intervention; Kinetics; Laboratory Animals; Lead; Lung; Macaca mulatta; Maintenance; Measures; Modeling; Monkeys; Morbidity - disease rate; Persons; Postherpetic neuralgia; Primates; Production; Regulatory T-Lymphocyte; Resolution; Risk Factors; Role; Sensory Ganglia; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Vaccines; Vascular Diseases; Viral Antigens; Viremia; Virus; Virus Diseases; Virus Latency; Virus Replication; age related; aged; cellular development; cytokine; design; improved; in vivo; juvenile animal; lytic replication; mortality; nonhuman primate; novel; pathogen; prevent; public health relevance; response; senescence; virus development; virus pathogenesis

DESCRIPTION (provided by applicant): Reactivation of latent varicella zoster virus (VZV) leads to herpes zoster (HZ, also known as shingles), a disease that causes major morbidity and occasionally mortality in older individuals. The incidence of HZ increases from 3.3 per 1000 person-years at age 40-49 to 7.7 at age 60-69. Advanced age is the primary risk factor not only for developing HZ, but also complications such as post herpetic neuralgia, vasculopathies and zoster opthalmicus. Current estimates predict that by 2020 more than 70 million Americans will be over the age of 65 therefore, the incidence of HZ and associated complications will certainly increase. Furthermore, the currently approved vaccine against HZ reduces the incidence of shingles by only 51%. Thus, a significant portion of the vaccine recipients still remains susceptible to VZV reactivation. A major obstacle in developing better treatments and vaccines for HZ is that models utilizing VZV infection of laboratory animals do not produce signs of in clinical disease that occur in humans. Consequently, our understanding of the immune correlates of protection against VZV infection and reactivation remains very limited due to lack of a suitable animal model to study host-pathogen interactions in vivo. We have developed a nonhuman primate model wherein young rhesus macaques infected with a primate homologue of human VZV, simian varicella virus (SVV) display the hallmarks of VZV infection in humans; i.e., the appearance of generalized varicella rash, the development of cellular and humeral immunity, and the establishment of latency with limited transcriptional activity in sensory ganglia. In contrast to young rhesus macaques, aged animals infected with SVV remain persistently viremic. In aged monkeys, persistent lytic replication occurred despite the development of an IgG antibody response that was comparable to that generated by young animals. On the other hand, SVV-specific T cell responses in aged animals were significantly delayed compared to those generated by young animals. These data strongly suggest that, as described for VZV, defects in T cell responses in aged animals result in poor immunological control of SVV replication and dissemination. Further evidence for this hypothesis was obtained from young rhesus macaques depleted of either CD4 or CD8 T cells and then infected with SVV. In CD8 T cell-depleted animals, SVV antigen was persistently detected in the lungs despite presence of a comparable IgG response to non-depleted controls. In CD4 T cell-depleted animals, the IgG response was significantly delayed and reduced. However, although IgG titers reached comparable levels as the controls in one CD4 T cell-depleted animal, it remained persistently viremic nevertheless. These data strongly suggest that, as described for VZV, the development and maintenance of a robust T cell response is critical to the control of SVV infection. Therefore, SVV infection of young and aged rhesus macaques provides a unique opportunity to: (1) identify age-related differences in the SVV-specific T cell responses and (2) determine how these differences in immune responses affect the aged animal's ability to control SVV replication and to maintain latency. These studies will improve our understanding of immunological control of latent VZV as well as other latent pathogens that pose significant health issues for the elderly. PUBLIC HEALTH RELEVANCE: Herpes zoster (HZ), or shingles, is caused by reactivation of latent varicella zoster virus (VZV) and causes significant morbidity and sometimes mortality in the elderly. Although it is generally believed that decreased T cell immunity is the underlying cause of HZ, the specific defects remain poorly understood. In this application, we will employ a novel and robust nonhuman primate model of VZV infection to improve our understanding of the immune control of VZV in the aged, a prerequisite for designing better vaccines and treatment to prevent HZ and other latent pathogens in the elderly.

描述（由申请人提供）：潜伏的水痘带状疱疹病毒（VZV）的重新激活会导致带状疱疹（HZ，也称为带状疱疹），这是一种导致老年人严重发病甚至偶尔死亡的疾病。带状疱疹的发病率从 40-49 岁每千人年 3.3 例增加到 60-69 岁每千人年 7.7 例。高龄不仅是带状疱疹发生的主要危险因素，也是带状疱疹后神经痛、血管病变和眼部带状疱疹等并发症的主要危险因素。目前估计，到 2020 年，超过 7000 万美国人将超过 65 岁，因此，带状疱疹和相关并发症的发病率肯定会增加。此外，目前批准的带状疱疹疫苗只能将带状疱疹的发病率降低 51%。因此，很大一部分疫苗接种者仍然对 VZV 重新激活敏感。开发更好的带状疱疹治疗方法和疫苗的一个主要障碍是，利用实验动物感染水带状疱疹病毒的模型不会产生人类发生的临床疾病的迹象。因此，由于缺乏合适的动物模型来研究体内宿主-病原体相互作用，我们对水痘带状疱疹病毒感染和再激活的免疫相关性的理解仍然非常有限。 我们开发了一种非人类灵长类动物模型，其中感染人类 VZV 灵长类同源物猿水痘病毒 (SVV) 的年轻恒河猴显示出人类 VZV 感染的特征；即，全身水痘皮疹的出现、细胞和肱骨免疫的发展以及感觉神经节中转录活性有限的潜伏期的建立。与年轻的恒河猴相比，感染 SVV 的老年动物仍持续存在病毒血症。在老年猴子中，尽管产生了与年轻动物相当的 IgG 抗体反应，但仍发生了持续的裂解复制。另一方面，与年轻动物相比，老年动物的 SVV 特异性 T 细胞反应明显延迟。这些数据强烈表明，正如 VZV 所描述的那样，老年动物 T 细胞反应缺陷导致 SVV 复制和传播的免疫控制较差。这一假设的进一步证据是从清除了 CD4 或 CD8 T 细胞然后感染 SVV 的年轻恒河猴中获得的。在 CD8 T 细胞耗尽的动物中，尽管存在与未耗尽的对照动物相当的 IgG 反应，但在肺部持续检测到 SVV 抗原。在 CD4 T 细胞耗尽的动物中，IgG 反应显着延迟和降低。然而，尽管一只 CD4 T 细胞耗尽的动物的 IgG 滴度达到了与对照相当的水平，但它仍然持续存在病毒血症。这些数据强烈表明，正如 VZV 所描述的那样，强大的 T 细胞反应的发展和维持对于控制 SVV 感染至关重要。因此，年轻和老年恒河猴的 SVV 感染提供了一个独特的机会：（1）识别 SVV 特异性 T 细胞反应中与年龄相关的差异；（2）确定这些免疫反应差异如何影响老年动物控制 SVV 复制和维持潜伏期的能力。这些研究将提高我们对潜在水痘带状疱疹病毒以及对老年人造成重大健康问题的其他潜在病原体的免疫控制的理解。 公共卫生相关性：带状疱疹 (HZ) 或带状疱疹是由潜伏的水痘带状疱疹病毒 (VZV) 重新激活引起的，会导致老年人显着发病，有时甚至导致死亡。尽管人们普遍认为 T 细胞免疫力下降是带状疱疹的根本原因，但具体缺陷仍知之甚少。在此应用中，我们将采用一种新颖且稳健的非人灵长类水痘带状疱疹病毒感染模型，以提高我们对老年人水痘带状疱疹病毒免疫控制的了解，这是设计更好的疫苗和治疗方法以预防老年人带状疱疹和其他潜在病原体的先决条件。