Mechanisms of varicella virus-induced multisystem disease using a primate model

使用灵长类动物模型研究水痘病毒诱导的多系统疾病的机制

• 批准号: 10542748
• 负责人: RAVI MAHALINGAM
• 金额: $ 96.6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542748
• 关键词: Adrenal Glands; Affect; Age Years; American; Animals; Apoptosis; Arteries; Autoimmune Diseases; Biological Assay; Biopsy; Blindness; Blood; Blood Vessels; Bronchoalveolar Lavage; Burning Mouth Syndrome; CXCL10 gene; Cell Separation; Cells; Cellular Assay; Chickenpox; Chronic; Clinical; Detection; Development; Disease; Down-Regulation; Elderly; Enzyme-Linked Immunosorbent Assay; Esophagitis; Euthanasia; Exanthema; Fibroblasts; Flow Cytometry; Frequencies; Ganglia; Gastroparesis; Genetic Transcription; Health Care Costs; Herpes zoster disease; Herpesvirus Type 3; Human; IL8 gene; Immune; Immune response; Immunocompromised Host; Immunofluorescence Immunologic; Immunosuppression; In Vitro; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Lung; Lymphadenitis; Macaca; Macaca mulatta; Macrophage; Major Histocompatibility Complex; Matrix Metalloproteinases; Modeling; Monkeys; Multi-Infarct Dementia; Organ; Pain; Pathologic; Pathway interactions; Patients; Phenotype; Play; Population; Postherpetic neuralgia; Primary Infection; Primates; Production; Protocols documentation; Pulmonary Inflammation; Quality of life; RNA; Rhesus; Role; Sampling; Skin; Stains; Stroke; Suicide; System; T cell infiltration; T-Lymphocyte; Tacrolimus; Techniques; Temporal Arteritis; Testing; Time; Tissues; Vasculitis; Viral; Viral Antigens; Viremia; Virus; Virus Diseases; Virus Replication; body system; burden of illness; cerebral artery; clinically relevant; cytokine; immune activation; immune cell infiltrate; immune function; inflammatory marker; insight; lymph nodes; monocyte; neutrophil; nonhuman primate; novel; prevent; programmed cell death ligand 1; receptor; transcriptome; transcriptome sequencing; varicella zoster virus vasculopathy

By 2050, the number of Americans 65 years and older is projected to be 83.7 million, and the burden of diseases and healthcare costs will be staggering. An important cause of multi-system disease in the elderly is varicella zoster virus (VZV) reactivation. More than 95% of humans harbor latent VZV in their ganglia following primary infection (varicella, chickenpox) and 50% of them will reactivate VZV by 85 years of age. Serious complications of VZV reactivation include postherpetic neuralgia (PHN), giant cell arteritis, burning mouth syndrome, stroke, multi-infarct dementia, blindness, esophagitis, pneumonitis, and gastroparesis. Thus, VZV reactivation affects multiple organs. VZV-induced persistent inflammation has emerged as an important pathologic contributor in most of these disorders. The mechanism(s) by which inflammatory cells persist in infected tissue is unknown; however human vascular cells infected in vitro with VZV show downregulated expression of programmed death ligand 1 (PD-L1) and major histocompatibility complex 1. Decreased PD-L1 expression contributes to persistent inflammation in autoimmune diseases, raising the possibility that VZV- induced downregulation of PD-L1 also contributes to persistent inflammation. Since VZV is an exclusively human virus, we will investigate the role of virus-induced PD-L1 dysregulation across multiple, clinically relevant tissues in non-human primates infected with simian varicella virus (SVV), a model that we developed in the last two decades. SVV, the primate counterpart of VZV, causes varicella on primary infection, establishes latency in ganglia, and reactivates later to produce zoster and multi-system disease. Preliminary results reveal SVV antigen- and CXCL10-induced T cell infiltration in ganglia 4 months after tacrolimus- induced SVV reactivation in rhesus macaques, similar to the chronic ganglionitis seen in PHN patients. Like VZV, SVV infection of rhesus fibroblasts in culture leads to decreased PD-L1 expression. Thus, we hypothesize that after SVV reactivation, viral antigen and activated immune cells persist in multiple tissues for months, in part due to dysregulation of PD-L1, thereby contributing to clinical disease seen in inflamed tissue in the elderly. To test our hypothesis, we will analyze the extent of SVV infection and associated inflammation in multiple tissues longitudinally after zoster (Aim 1). We will also correlate the composition, activation state and function of immune cells in multiple tissues longitudinally after zoster with the presence of SVV and inflammation (Aim 2). Overall, these studies in the non-human primate model of VZV reactivation will provide insight into multiple virus-infected tissues, not available in humans, to elucidate the mechanisms of viral persistence and inflammation, information that will be translatable to development of new intervention strategies to inhibit multi-system disease caused by VZV in elderly humans.

到2050年，65岁及以上的美国人的数量预计将达到8370万，而负担