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: 8847630
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847630
• 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(申请人提供)：与年轻人群相比，许多病毒感染在老年人中更为严重。这一点在2002-2003年爆发的严重急性呼吸综合征(SARS)中得到了显著的体现，当时60岁以上的患者中有50%死亡，而24岁以下的患者中没有死亡。在感染非典型肺炎冠状病毒(SARS-CoV)的小鼠中，也观察到几乎相同的高度年龄依赖性的易感性，使其成为识别老龄小鼠宿主免疫反应缺陷的有用模型。我们的初步结果表明，在老年SARS冠状病毒感染的小鼠中，呼吸树突状细胞(RDC)向引流淋巴结(DLN)的迁移存在缺陷，导致抗病毒T细胞反应差，病毒清除差，肺损伤增加，死亡率增加。Poly I：C的预治疗逆转了在这些老年感染小鼠中观察到的发病率和死亡率的增加。这一建议的中心假设是，RDC功能和随后的T细胞反应的年龄相关性变化是老年呼吸道病毒感染人群观察到的不良结果的关键。这一目标将通过以下具体目标来实现。目的1.确定感染SARS冠状病毒的12-14M小鼠的缺陷T细胞反应在多大程度上是T细胞固有的。RDC向DLN迁移的缺陷抑制了强大的T细胞反应的产生，但这一观察不能排除导致严重疾病的额外的T细胞固有缺陷。这种可能性将得到调查。目的2.探讨老年小鼠肾树突状细胞功能障碍的发病基础和发病时间。这一目标的目的将是确定感染SARS冠状病毒的老年小鼠是否存在RDC功能的额外缺陷，并确定这些缺陷的基础。对具有保护作用的Poly I：C的作用机制进行了研究。最后，将分析特定脂质介质如前列腺素E2的功能随年龄的变化，这些介质对于RDC向DLN的有效迁移至关重要。目的3.确定呼吸道病原体感染老年小鼠是否普遍存在RDC功能缺陷。该提案的一个关键目标是通过确定感染其他呼吸道病毒的小鼠的RDC功能和随之而来的抗病毒T细胞反应是否受到影响，来检验我们结果的一般性，这些病毒包括甲型流感病毒、呼吸道合胞病毒或MHV-1，一种嗜肺性小鼠冠状病毒。确定RDC缺陷是增加对病毒呼吸道感染易感性的关键，将为感染患者提供一个新的治疗靶点。