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: 8663180
• 负责人: Stanley Perlman
• 金额: $ 37.75万
• 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: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663180
• 关键词: Acute; Acute Lung Injury; Address; Age; Agonist; Animal Model; Animals; Cell physiology; Cells; Cessation of life; Clinical; Coronavirus; Defect; Dendritic Cells; Dendritic cell activation; Dependence; Development; Dinoprostone; Disease; Disease Outbreaks; Elderly; Employee Strikes; Exhibits; Functional disorder; Generations; Goals; Grant; Immune response; Inbred BALB C Mice; Individual; Infection; Influenza A virus; Lung; Lung diseases; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Patients; Poly I-C; Population; Predisposition; Principal Investigator; Prostaglandins; Regulatory T-Lymphocyte; Reporting; Respiratory Tract Infections; Respiratory physiology; Respiratory syncytial virus; Role; Series; Severe Acute Respiratory Syndrome; Severity of illness; T cell response; T-Lymphocyte; Time; Viral; Virus; Virus Diseases; West Nile virus; age related; aged; base; cell motility; improved; lipid mediator; lymph nodes; migration; mortality; new therapeutic target; novel; pathogen; programs; research study; respiratory; respiratory infection virus; respiratory virus

DESCRIPTION (provided by applicant): Many viral infections are more severe in aged compared to young populations. This was strikingly illustrated in the 2002-2003 outbreak of the Severe Acute Respiratory Syndrome (SARS), in which >50% of patients who were over 60 year old died while no deaths occurred in those under 24 years. A nearly identical steep age dependence in susceptibility is also observed in mice infected with mouse-adapted strains of SARS-coronavirus (SARS-CoV), making this a useful model for identifying defects in the host immune response in aged mice. Our preliminary results suggest that migration of respiratory dendritic cells (rDC) to draining lymph nodes (DLN) is defective in aged SARS-CoV-infected mice, resulting in a poor anti-virus T cell response, poor virus clearance and increased lung damage as well as increased mortality. Pre-treatment with poly I:C reverses the increased morbidity and mortality observed in these aged infected mice. The central hypothesis of this proposal is that age-dependent changes in rDC function and subsequent T cell responses are critical for the poor outcomes observed in aged populations with respiratory virus infections. This objective will be approached in the following specific aims. Aim 1. To determine the extent to which the defective T cell response in SARS-CoV- infected 12-14m mice is T cell-intrinsic. Defects in rDC migration to the DLN inhibit the generation of a robust T cell response, but this observation does not preclude additional T cell- intrinsic defects contributing to severe disease. This possibility will be investigated. Aim 2. To investigate the basis and time of onset of rDC dysfunction in old mice. The goals of this aim will be to determine if additional defects in rDC function exist in SARS-CoV-infected aged mice and determine the basis of these defects. The mechanism of action of poly I:C, which is protective, will be investigated. Finally, age-dependent changes in the function of specific lipid mediators such as prostaglandin E2, which are critical for efficient rDC migration to DLN, will be analyzed. Aim 3. To determine whether defective rDC function is common in aged mice infected with respiratory pathogens. A key goal of the proposal is to examine the generality of our results by determining whether rDC function and consequent anti-virus T cell responses are compromised in mice infected with other respiratory viruses, such as influenza A virus, respiratory syncytial virus or MHV-1, a pneumotropic murine coronavirus. Identification of rDC defects as critical in the increased susceptibility to viral respiratory infections will provide a novel therapeutic target in infected patients.

描述（由申请人提供）：与年轻人群相比，许多病毒感染的年龄更严重。这在2002 - 2003年严重的急性呼吸综合症（SARS）的爆发中得到了明显说明，其中60岁以上的患者中，> 50％的患者死亡，而24岁以下的患者没有死亡。在感染了小鼠适应的SARS-核纳病毒（SARS-COV）的小鼠中，也观察到敏感性几乎相同的陡峭年龄依赖性，这使得这是鉴定老年小鼠宿主免疫反应中缺陷的有用模型。我们的初步结果表明，呼吸道树突状细胞（RDC）迁移到排水淋巴结（DLN）中，在老年SARS-COV感染的小鼠中有缺陷，导致抗病毒T细胞反应较差，病毒清除率较差，肺部损害增加以及死亡率增加。用Poly I：C进行预处理可逆转这些年龄感染小鼠中观察到的发病率和死亡率的增加。该提议的中心假设是，RDC功能的年龄依赖性变化，随后的T细胞反应对于患有呼吸道病毒感染的年龄群体中观察到的不良结局至关重要。该目标将在以下特定目标中实现。目的1。确定在SARS-COV感染的12-14m小鼠中有缺陷的T细胞反应的程度是T细胞中的。 RDC向DLN迁移的缺陷抑制了强大的T细胞反应的产生，但是该观察结果并不排除导致严重疾病的其他T细胞内在缺陷。这种可能性将被调查。目标2。研究旧小鼠RDC功能障碍的基础和时间。该目的的目标是确定在SARS-COV感染的老年小鼠中是否存在RDC功能中的其他缺陷，并确定这些缺陷的基础。将研究Poly I：C的作用机理，具有保护性。最后，将分析特定脂质介质（例如前列腺素E2）的功能的变化，这对于有效的RDC迁移至DLN至关重要。目标3。确定在感染呼吸道病原体的老年小鼠中是否常见RDC功能是否常见。该提案的一个关键目的是通过确定RDC功能和随之而来的抗病毒T细胞反应是否在感染其他呼吸道病毒的小鼠中损害，例如流感病毒，呼吸道合成病毒或MHV-1，Pneumotropic murine coronaravirus。鉴定RDC缺陷对于增加病毒呼吸道感染的敏感性至关重要，将为感染患者提供新的治疗靶点。