Effect of aging on neuroinvasion during West Nile virus (WNV) infection.

衰老对西尼罗河病毒（WNV）感染期间神经侵袭的影响。

• 批准号: 9750522
• 负责人: Michael S Diamond
• 金额: $ 15.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750522
• 关键词: Acute; Adolescent; Adult; Age; Aging; Animals; Antigen-Presenting Cells; Antiviral Agents; Antiviral Response; Apoptosis; Arthropods; Autoimmune Process; Award; B-Lymphocytes; Blood; Blood - brain barrier anatomy; Body Weight decreased; Breeding; C57BL/6 Mouse; Cell Count; Cell Death; Cells; Cohort Studies; Development; Diamond; Disease; Disease Progression; Dose; Drowsiness; Elderly; Encephalitis; Fever; Flavivirus; Fostering; Immune; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Immunologics; Impairment; Individual; Infection; Infection Control; Inflammation; Inflammatory; Invaded; Kinetics; Laboratories; Lead; Leukocyte Trafficking; Link; Lymphocyte; Lymphoid; Lymphoid Tissue; Meningitis; Molecular; Mus; Natural Immunity; Neuraxis; New York; Organ; Paralysed; Pattern; Peripheral; Permeability; Phase; Phenotype; Predisposition; Prevention strategy; Respiratory distress; Rodent Model; Skin; Spleen; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; Tissues; Tremor; United States; Viral; Viral Load result; Viremia; Virulent; Virus; Virus Diseases; Virus Replication; West Nile Encephalitis; West Nile viral infection; West Nile virus; Work; adaptive immune response; adaptive immunity; age effect; aged; animal old age; antiviral immunity; cohort; cytokine; flu; immunoregulation; improved; lymph nodes; mouse model; nervous system disorder; neuroinflammation; neurotropic; pathogen; pathogenic virus; recruit; response; virology

Aging is associated with dysregulation of innate and adaptive immunity, which impairs an individual's ability to control infection by newly encountered pathogens. Aging also impacts neuroprotective mechanisms within the central nervous system (CNS), including the function of the blood-brain barrier (BBB), which limits the entry and replication of neutrotropic viruses. West Nile virus (WNV) is the leading cause of arthropod-transmitted viral infections in the United States. While most WNV infections are asymptomatic, individuals with symptomatic disease present either with a flu-like febrile illness that can progress to severe neuroinvasive diseases including meningitis, encephalitis, or flaccid paralysis. Severe WNV infection, especially fatal forms, predominate in the elderly. It is unclear whether this is due to effects of aging on viral invasion and/or virologic control within peripheral tissues or the CNS. To study many different aspects of immune regulation in adult mice, the Diamond and Klein laboratories have established a murine model of infection with a virulent WNV strain. However, interactions between antiviral immunity, neuroinflammation, and aging within the CNS have not been investigated. In this proposal, we will examine the impact of age on innate and adaptive immune mechanisms that control viral entry and clearance specifically within the CNS. The UH2 phase we will establish breeding cohorts and determine the feasibility of using 21 month-old aged animals in WNV infection studies. In the UH3 phase, we will explore how changes in skin immunity, BBB integrity, and CNS inflammation during aging influence neuroinvasion and disease progression associated with WNV infection.

衰老与先天免疫和适应性免疫的失调有关，这损害了个体控制新遇到的病原体感染的能力。衰老还影响中枢神经系统（CNS）内的神经保护机制，包括血脑屏障（BBB）的功能，这限制了嗜热病毒的进入和复制。西尼罗河病毒（WNV）是美国节肢动物传播病毒感染的主要原因。虽然大多数西尼罗河病毒感染是无症状的，但有症状疾病的个体要么表现为流感样发热性疾病，可进展为严重的神经侵入性疾病，包括脑膜炎，脑炎或弛缓性麻痹。严重的西尼罗河病毒感染，特别是致命的形式，主要发生在老年人。目前尚不清楚这是否是由于衰老对病毒入侵和/或外周组织或CNS内病毒控制的影响。为了研究成年小鼠免疫调节的许多不同方面，Diamond和Klein实验室建立了一种感染WNV强毒株的小鼠模型。然而，抗病毒免疫，神经炎症和中枢神经系统内的衰老之间的相互作用尚未研究。在这个提议中，我们将研究年龄对先天性和适应性免疫机制的影响，这些免疫机制控制病毒进入和清除中枢神经系统。在UH 2阶段，我们将建立繁殖队列，并确定在WNV感染研究中使用21月龄动物的可行性。在UH 3阶段，我们将探讨衰老过程中皮肤免疫、血脑屏障完整性和中枢神经系统炎症的变化如何影响与西尼罗河病毒感染相关的神经侵袭和疾病进展。