Effect of immunosenescence on innate immune responses to RSV

描述(由申请人提供)：长期以来，免疫系统中与年龄相关的变化被归因于适应性免疫反应的下降。现在越来越多的人认识到免疫衰老还涉及到先天免疫系统功能的显著变化。然而，由于人类研究的局限性和适当的免疫衰老动物模型的缺乏，年龄增长对先天免疫反应的影响很难评估。我们已经建立了一种老年棉鼠呼吸道合胞病毒(RSV)感染模型。呼吸道合胞病毒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。老年棉鼠RSV病模型的特点是病毒从肺清除延迟，肺细胞因子表达倾斜，肺内粒细胞募集改变，中性粒细胞趋化因子失衡。这些变化表明，在RSV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(与RSV清除有关的细胞)的功能与年龄有关。这项建议将在生理(肺)、细胞(巨噬细胞和中性粒细胞)和分子(细胞因子/趋化因子反应，包括I型干扰素)水平上研究针对RSV的先天免疫反应随着年龄的增长而发生的变化。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特定影响。 公共卫生相关性：呼吸道合胞病毒(RSV)是幼儿的主要呼吸道病毒病原体，也是导致婴儿死亡的主要病毒原因。近年来，RSV也被认为是人类老年人的一种严重健康风险。老年呼吸道合胞病毒病表现为一种特别严重的形式的原因尚不清楚。我们已经建立了一种老年棉鼠RSV病模型，其特征是病毒清除延迟，细胞因子产生扭曲，细胞对病毒的炎症反应改变。棉花鼠目前是唯一一种免疫衰老被证明影响RSV早期抗病毒反应的小型动物模型。现在将探索这个模型来确定免疫衰老对病毒的先天免疫反应的影响，特别是干扰素反应的作用以及巨噬细胞和中性粒细胞的功能。

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.