Effect of immunosenescence on innate immune responses to RSV

免疫衰老对 RSV 先天免疫反应的影响

• 批准号: 8194503
• 负责人: Marina S Boukhvalova
• 金额: $ 22.76万
• 依托单位: SIGMOVIR BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8194503
• 关键词: Effect; immunosenescence; innate; immune; responses

DESCRIPTION (provided by applicant): Age-related changes in immune system have long been attributed to the decline in the adaptive immune responses. Now it is becoming increasingly recognized that immunosenescence also involves significant alterations in the function of innate immune system. The impact of advancing age on innate immune responses, however, is difficult to assess due to the limitations of human studies and scarcity of appropriate animal models of immunosenescence. We have previously established an aged cotton rat S.hispidus model of Respiratory Syncytial Virus (RSV) infection. RSV is the primary cause of severe lower respiratory tract infection in infants and young children. Recently RSV has also been recognized as a serious health risk in the elderly. The aged cotton rat model of RSV disease is characterized by delayed viral clearance from the lungs, skewed patterns of pulmonary cytokine expression, alterations in pulmonary recruitment of granulocytes, and neutrophil chemokine imbalance. These changes point to age-related alterations in the function of macrophages (an important source of pro-inflammatory cytokines) and neutrophils (cells implicated in RSV clearance) in the cotton rat model of RSV disease. This proposal will address changes in the innate immune responses to RSV developing with age at the physiological (lung), cellular (macrophages and neutrophils), and molecular (cytokine/chemokine responses including type I interferon) levels using the cotton rat S.hispidus model. Most importantly, we will establish a valuable animal model for studying specific effects of aging on innate immune responses to human viral infections. PUBLIC HEALTH RELEVANCE: Respiratory Syncytial Virus (RSV) is the major respiratory viral pathogen of young children and is the primary viral cause of death in infants. Recently RSV has also been recognized as a serious health risk in human elderly. The reasons why RSV disease in the elderly takes on a particularly severe form is not known. We have established an aged cotton rat model of RSV disease which is characterized by delayed viral clearance, skewed cytokine production, and altered cellular inflammatory response to the virus. The cotton rat currently represents the only small animal model for which immunosenescence was shown to affect early antiviral response to RSV. This model will now be explored to define effect of immunosenescence on the innate immune responses to the virus, with particular focus on the role of interferon response and function of macrophages and neutrophils.

描述（由申请方提供）：长期以来，免疫系统中与免疫缺陷相关的变化被归因于适应性免疫应答的下降。现在越来越多的人认识到，免疫衰老也涉及先天免疫系统功能的显著改变。然而，由于人类研究的局限性和缺乏适当的免疫衰老动物模型，很难评估年龄增长对先天免疫反应的影响。我们以前建立了呼吸道合胞病毒（RSV）感染的老年棉鼠S.hispidus模型。RSV是婴幼儿严重下呼吸道感染的主要原因。最近，RSV也被认为是老年人的严重健康风险。RSV疾病的老年棉鼠模型的特征在于延迟的病毒从肺中清除、肺细胞因子表达的偏斜模式、粒细胞的肺募集的改变和中性粒细胞趋化因子失衡。这些变化表明，在RSV疾病的棉鼠模型中，巨噬细胞（促炎细胞因子的重要来源）和中性粒细胞（参与RSV清除的细胞）的功能发生了年龄相关的变化。本提案将使用棉鼠S.hispidus模型，在生理（肺）、细胞（巨噬细胞和中性粒细胞）和分子（细胞因子/趋化因子应答，包括I型干扰素）水平上讨论对RSV的先天免疫应答随年龄增长而发生的变化。最重要的是，我们将建立一个有价值的动物模型，用于研究衰老对人类病毒感染的先天免疫反应的具体影响。 公共卫生关系：呼吸道合胞病毒（RSV）是幼儿的主要呼吸道病毒病原体，并且是婴儿死亡的主要病毒原因。最近，RSV也被认为是人类老年人的严重健康风险。RSV疾病在老年人中呈现特别严重形式的原因尚不清楚。我们已经建立了一个RSV疾病的老年棉鼠模型，其特征在于延迟的病毒清除，偏斜的细胞因子产生，和改变细胞对病毒的炎症反应。棉鼠是目前唯一一种被证明免疫衰老会影响对RSV的早期抗病毒反应的小动物模型。现在将探索该模型以确定免疫衰老对对病毒的先天免疫应答的影响，特别关注干扰素应答的作用以及巨噬细胞和中性粒细胞的功能。