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

抗 SARS-CoV T 细胞反应在发病机制中的作用

• 批准号: 8055138
• 负责人: Stanley Perlman
• 金额: $ 31.54万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055138
• 关键词: Address; Adoptive Transfer; Adult Respiratory Distress Syndrome; Animals; Cell Communication; Clinical; Coronavirus; Coronavirus Infections; Data; Defect; Dendritic Cells; Dendritic cell activation; Development; Disease; Goals; Homeostasis; Human; Immune response; Immune system; Immunodeficient Mouse; Inbred BALB C Mice; Infection; Instruction; Intervention; Lung; Lung diseases; Mediating; Modeling; Mus; Outcome; Pathogenesis; Population; Publishing; Relative (related person); Reporting; Resistance; Role; SCID Mice; Severe Acute Respiratory Syndrome; Severe Combined Immunodeficiency; Signal Transduction; Splenocyte; System; T cell response; T-Lymphocyte; Vaccination; Vaccines; Virus; Work; aged; arm; base; chemokine; cytokine; improved; juvenile animal; macrophage; mortality; pathogen; research study; response; vaccine development

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.

严重的急性呼吸道综合征（SARS）是一种冠状病毒引起的人类呼吸道疾病，死亡率为10％。老年人的死亡率尤其高。使用小鼠适应的Sarscov（MAI 5病毒），该版本在BALB/C小鼠中引起严重疾病，我们先前表明，在受感染的小鼠中，初始免疫反应在次优地激活，这又导致了延迟的抗病毒T细胞反应。我们还发现，肺抑制性巨噬细胞的消耗对于维持未感染的肺中稳态或活化的树突状细胞的继承转移导致肺免疫反应激活，增强的抗病毒T细胞反应和完全保护严重的临床疾病。该提案的核心目的是确定在没有其他干预措施的情况下，抗病毒T细胞反应的增强是否足以保护年轻的BALB/C小鼠免受严重疾病的影响，并研究定量和定性缺陷和定量缺陷以及像老年人一样对年龄较大的年龄小鼠的疾病是否有助于感染年轻动物。这些目标将在以下特定目的中实现：具体目的1。确定增强T细胞反应是否足以使年轻的BALB/C小鼠的最佳病毒清除率和保护侵害疾病。 在此目的中，将使用树突状细胞（DC）疫苗接种和病毒特异性T细胞转移到感染的BALB/C和免疫缺陷的小鼠中（SCID-Stevere组合的免疫缺陷）。具体目的2。确定效率低下的T细胞反应是否也是老年小鼠严重疾病的基础。该特定目的的目的是比较年轻和老年B6小鼠中T细胞反应的质量和数量，并确定老年小鼠反应的增强是否提供了保护。具体目的3。确定先天小鼠的先天性不良激活以及最终的T细胞反应的基础。 TLR信号的作用将在此目标中研究。 SARS领域的先前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，虽然天生的反应在容易患严重疾病的年轻小鼠和老年小鼠中受到很差的激活，但抗病毒T细胞反应对于改善预后可能是最重要的。提案完成后，我们将更好地了解SARS免疫反应的两个臂的相对重要性。