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

严重急性呼吸综合征(SARS)是一种由冠状病毒引起的人类呼吸道疾病，死亡率为10%。老年人口的死亡率尤其高。使用在BALB/c小鼠中引起严重疾病的SARSCoV(MAI5病毒)的小鼠适应版本，我们先前表明，在感染的小鼠中，初始免疫反应被激活，这反过来导致延迟的抗病毒T细胞反应。我们还发现，耗尽肺抑制性巨噬细胞，或过继转移激活的树突状细胞，可以激活肺免疫反应，增强抗病毒T细胞反应，并完全保护患者免受严重临床疾病的影响。这项建议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BALB/c小鼠免受严重疾病的影响，并调查数量和质量缺陷是否也会导致老年小鼠患病，因为老年小鼠与老年人一样，比年轻动物更容易受到感染。这些目标将在以下特定目标中实现：特定目标1.确定增强T细胞反应是否足以使幼年BALB/c小鼠获得最佳的病毒清除和疾病保护。 树突状细胞(DC)疫苗接种和将病毒特异性T细胞转移到感染的BALB/c和免疫缺陷小鼠(SCID-严重联合免疫缺陷)中将用于这一目的。具体目的2.确定低效T细胞反应是否也是老年小鼠严重疾病的基础。这一特定目标的目的将是比较年轻和老年B6小鼠T细胞反应的质量和数量，并确定增强老年小鼠的反应是否提供保护。具体目的3.确定老年B6小鼠先天T细胞活性差的基础，并最终确定T细胞反应。为了达到这个目的，我们将研究TLR信号的作用。以前在SARS领域的工作强调了先天免疫反应在保护中的重要性。我们的结果表明，尽管在易患严重疾病的年轻和老年小鼠中，先天反应被激活得很差，但抗病毒T细胞反应可能是改善结果最关键的。在建议完成后，我们将更了解免疫反应这两只手臂在SARS中的相对重要性。

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.