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

描述（由申请人提供）：与年轻人相比，许多病毒感染在老年人中更为严重。这在2002-2003年爆发的严重急性呼吸系统综合症（SARS）中得到了明显的说明，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。在感染小鼠适应的sars冠状病毒株（SARS-CoV）的小鼠中，也观察到几乎相同的易感性的急剧年龄依赖性，使其成为识别老年小鼠宿主免疫反应缺陷的有用模型。我们的初步结果表明，呼吸道树突状细胞（rDC）向引流淋巴结（DLN）的迁移在老年sars - cov感染小鼠中存在缺陷，导致抗病毒T细胞反应差，病毒清除差，肺损伤增加以及死亡率增加。poly I:C预处理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。该建议的中心假设是，rDC功能的年龄依赖性变化和随后的T细胞反应是呼吸道病毒感染老年人群中观察到的不良结果的关键。这一目标将在下列具体目标中实现。目的1。确定感染SARS-CoV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T细胞反应的产生，但这一观察结果并不能排除额外的T细胞内在缺陷导致严重疾病的可能性。我们将调查这种可能性。目标2。探讨老年小鼠rDC功能障碍发生的基础和时间。这一目的的目标将是确定在感染sars - cov的老年小鼠中是否存在rDC功能的其他缺陷，并确定这些缺陷的基础。研究了具有保护作用的聚I:C的作用机理。最后，将分析特定脂质介质（如前列腺素E2）功能的年龄依赖性变化，这对于rDC向DLN的有效迁移至关重要。目标3。确定感染呼吸道病原体的老年小鼠rDC功能缺陷是否普遍存在。该提案的一个关键目标是通过确定感染其他呼吸道病毒（如甲型流感病毒、呼吸道合胞病毒或嗜肺性小鼠冠状病毒MHV-1）的小鼠的rDC功能和随后的抗病毒T细胞反应是否受损，来检查我们结果的普遍性。识别rDC缺陷是增加呼吸道病毒感染易感性的关键因素，将为感染患者提供新的治疗靶点。

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.