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.