Role of anti-SARS-CoV T cell response in pathogenesis

严重急性呼吸系统综合症（SARS）是一种冠状病毒引起的人类呼吸道疾病，死亡率为10%。老年人口的死亡率特别高。使用小鼠适应的SARSCoV （MAI 5病毒）在BALB/c小鼠中引起严重疾病，我们先前表明，在感染小鼠中初始免疫反应被激活，这反过来导致抗病毒T细胞反应延迟。我们还发现，肺抑制性巨噬细胞的耗竭或活化树突状细胞的过继转移可激活肺免疫反应，增强抗病毒T细胞反应并完全保护肺部免受严重临床疾病的侵袭。本提案的中心目标是确定在没有其他干预措施的情况下，增强抗病毒T细胞反应是否足以保护年轻的BALB/c小鼠免受严重疾病的侵害，并调查定量和定性缺陷是否也会导致老年小鼠的疾病，老年小鼠与老年人一样，比年轻动物更容易受到感染。这些目标将在以下具体目标中实现：确定增强T细胞反应是否足以在年轻BALB/c小鼠中获得最佳的病毒清除和疾病保护。

Severe Acute Respiratory Syndrome (SARS) is a coronavirus-induced human respiratory disease with a 10% mortality. Mortality is especially high in aged populations. Using a mouse-adapted version of SARSCoV (MAI 5 virus) that causes severe disease in BALB/c mice, we previously showed that the initial immune response is activated suboptimally in infected mice and this resulted, in turn, in a delayed anti-virus T cell response. We also found that depletion of lung inhibitory macrophages, important for maintaining homeostasis in the uninfected lung, or adoptive transfer of activated dendritic cells resulted in activation of the pulmonary immune response, an enhanced anti-virus T cell response and complete protection from severe clinical disease. The central objectives of this proposal are to determine whether enhancement of the anti-virus T cell response, in the absence of other interventions, is sufficient to protect young BALB/c mice from severe disease and to investigate whether quantitiative and qualitative defects also contribute to disease in aged mice, which like older humans, are more susceptible to infection than young animals. These objectives will be approached in the following specific aims: Specific aim 1. To determine if enhancing the T cell response is sufficient for optimal virus clearance and protection from disease in young BALB/c mice. Dendritic cell (DC) vaccination and transfer of virus-specific T cells into infected BALB/c and immunodeficient mice (SCID-severe combined immunodeficiency) will be used in this aim. Specific aim 2. To determine if an inefficient T cell response is also the basis for severe disease in aged mice. The goal of this specific aim will be compare the quality and quantity of the T cell response in young and aged B6 mice and determine whether enhancement of the response in aged mice affords protection. Specific aim 3. To determine the basis of the poor activation of the innate, and ultimately, the T cell response in aged B6 mice. The role of TLR signaling will be investigated in this aim. Previous work in the SARS field has emphasized the importance of the innate immune response in protection. Our results suggest that while the innate response is poorly activated in young and aged mice prone to severe disease, the anti-virus T cell response may be most critical for improved outcomes. At the completion of the proposal, we will better understand the relative importance of the two arms of the immune response in SARS.