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: 8658360
• 负责人: Ilhem Messaoudi
• 金额: $ 36.23万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658360
• 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.

描述(申请人提供)：潜伏的水痘带状疱疹病毒(VZV)重新激活会导致带状疱疹(HZ，也称为带状疱疹)，这是一种在老年人中导致主要发病率和偶尔死亡的疾病。HZ的发病率从40-49岁时的3.3/1000人年增加到60-69岁时的7.7/1000人年。高龄不仅是HZ发病的主要危险因素，也是带状疱疹后遗神经痛、血管病变和眼带状疱疹等并发症的主要危险因素。目前的估计预测，到2020年，65岁以上的美国人将超过7000万，因此，HZ及其相关并发症的发生率肯定会增加。此外，目前批准的针对HZ的疫苗仅将带状疱疹的发病率降低了51%。因此，很大一部分疫苗接受者仍然容易受到VZV重新激活的影响。开发更好的HZ治疗方法和疫苗的一个主要障碍是，利用实验室动物感染VZV的模型不能产生人类临床疾病的迹象。因此，由于缺乏合适的动物模型来研究体内宿主和病原体的相互作用，我们对预防VZV感染和重新激活的免疫相关性的了解仍然非常有限。我们建立了一个非人类灵长类动物模型，在这个模型中，幼年恒河猴感染了人VZV的灵长类同源物，猴水痘病毒(SVV)在人类中表现出VZV感染的特征：即出现泛发性水痘皮疹，细胞和体液免疫的发展，以及感觉神经节中转录活性有限的潜伏期的建立。与年轻的恒河猴不同，感染了SVV的老年动物仍然持续感染病毒。在老年猴子中，尽管产生了与年轻动物产生的免疫球蛋白抗体反应相当的免疫球蛋白抗体反应，但仍发生了持续的裂解复制。另一方面，与幼年动物相比，老年动物产生的SVV特异性T细胞反应明显延迟。这些数据强烈表明，正如对VZV所描述的那样，老年动物的T细胞反应缺陷导致了对SVV复制和传播的免疫控制不力。这一假说的进一步证据是从年轻的恒河猴身上获得的，这些猕猴失去了CD4或CD8T细胞，然后感染了SVV。在CD8T细胞耗竭的动物中，尽管存在与非耗尽对照类似的免疫球蛋白G反应，但在肺中仍持续检测到SVV抗原。在CD4T细胞耗尽的动物中，免疫球蛋白反应显著延迟和降低。然而，尽管在一只CD4T细胞耗尽的动物中，免疫球蛋白抗体效价达到了与对照组相当的水平，但它仍然持续存在病毒。这些数据有力地表明，正如对VZV所描述的那样，发展和维持强大的T细胞反应对于控制SVV感染至关重要。因此，幼年和老年恒河猴感染SVV提供了一个独特的机会：(1)确定与年龄相关的SVV特异性T细胞反应的差异；(2)确定这些免疫反应的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伏的VZV以及其他对老年人构成重大健康问题的潜伏病原体的免疫控制的理解。