SARS-CoV Proteins in Heterologous Viral Infection

异源病毒感染中的 SARS-CoV 蛋白

• 批准号: 6825519
• 负责人: John T Harty
• 金额: $ 33.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825519
• 关键词: Adenoviridae; B lymphocyte; MHC class I antigen; SARS virus; cellular immunity; cytotoxic T lymphocyte; dendritic cells; epitope mapping; genetically modified animals; host organism interaction; influenzavirus A; laboratory mouse; leukocyte activation /transformation; lung; microorganism immunology; monoclonal antibody; natural killer cells; pathologic process; recombinant virus; respiratory syncytial virus; severe acute respiratory syndrome; virus protein

The recent outbreak of Severe Acute Respiratory Syndrome (SARS) is a striking example of a potentially devastating emerging infectious disease. Although the initial SARS outbreak was contained through public health efforts, the epidemiology of respiratory virus infections in humans suggests that re-emergence of this disease is a distinct possibility. Unfortunately, current antiviral therapies did not prove effective in SARS patients. Thus, developing an effective vaccine is likely the best strategy for limiting this disease in the human population. The evidence to date is that SARS is caused by a human coronavirus (SARS-CoV), and the sequence of this virus has been determined. However, as useful as the molecular information may be for understanding the relationship of SARS-CoV to other coronaviruses, it is not sufficient to predict how the virus behaves in vivo and what elements of the virus will be targets for effective vaccination. Studies with respiratory virus infections suggest that disease pathogenesis may result from virus-mediated lysis of infected cells, the host immune response, or both. While limited, early studies with SARS patients reveal low, but constant levels of virus in the serum, during disease progression. This suggests that the immune system is contributing to the pathogenesis of disease. Alternatively, or in addition, the virus may evade the immune system in order to persist. Experimental systems to address SARS-CoV pathogenesis have not been described and very little is known about the immune response to SARS-CoV. In large part, the progress from molecular characterization of human viruses to vaccines is hampered by the lack of suitable small animal models for studies of pathogenesis and immune responses. The long-term goal of this project is to develop a mouse model to provide information on the pathogenesis and immune response to SARS-CoV that will be useful in designing vaccines to protect the population. We will address this long-term goal with the following specific aims: Aim 1. Characterize the specificity of the anti-SARS-CoV human CD8+ T cell response with HLA-A*201-transgenic mice and generate SARS-CoV protein-specific monoclonal antibodies. Aim 2. Determine if SARS-CoV proteins modulate adaptive immunity in the context of infection. Aim 3. Determine if SARS-CoV proteins modulate DC and NK immunity in the context of infection. Aim 4. Determine if SARS-CoV proteins modulate lung pathology in the context of infection.

最近爆发的严重急性呼吸系统综合症（SARS）是一种具有潜在破坏性的新出现的传染病的突出例子。虽然最初的SARS爆发是通过公共卫生努力控制的，但人类呼吸道病毒感染的流行病学表明，这种疾病再次出现的可能性很大。不幸的是，目前的抗病毒治疗在SARS患者中并没有证明有效。因此，开发一个 有效的疫苗可能是在人群中限制这种疾病的最佳策略。迄今为止的证据是SARS是由人类冠状病毒（SARS-CoV）引起的，并且该病毒的序列已经确定。然而，尽管分子信息可能有助于了解SARS-CoV与其他冠状病毒的关系，但不足以预测病毒在体内的行为以及病毒的哪些成分将成为目标 有效的疫苗接种。 对呼吸道病毒感染的研究表明，疾病的发病机制可能是由病毒介导的感染细胞裂解、宿主免疫反应或两者引起的。虽然有限，但对SARS患者的早期研究显示，在疾病进展期间，血清中的病毒水平较低，但恒定。这表明免疫系统对疾病的发病机制有贡献。或者，或另外，病毒可能会逃避免疫系统，以便持续存在。 研究SARS-CoV发病机制的实验系统尚未被描述，对SARS-CoV的免疫应答知之甚少。在很大程度上，从人类病毒的分子表征到疫苗的进展受到缺乏合适的小动物模型用于研究发病机制和免疫应答的阻碍。 该项目的长期目标是开发一种小鼠模型，以提供关于SARS-CoV的发病机制和免疫反应的信息，这将有助于设计保护人口的疫苗。我们将通过以下具体目标实现这一长期目标： 目标1.用HLA-A*201转基因小鼠表征抗SARS-CoV人CD 8 + T细胞应答的特异性，并产生SARS-CoV蛋白特异性单克隆抗体。 目标2.确定SARS-CoV蛋白是否在感染的背景下调节适应性免疫。 目标3.确定SARS-CoV蛋白在感染背景下是否调节DC和NK免疫。 目标4。确定SARS-CoV蛋白是否在感染的背景下调节肺病理学。