Control of T cell response during respiratory infection

描述（由申请人提供）：使用呼吸道病原体作为生物恐怖主义武器的威胁正在出现。因此，我们必须了解在肺的特殊微环境中病毒病原体与免疫反应的相互作用。虽然许多病原体构成威胁，但特别令人关切的是天花病毒。感染天花病毒不仅会导致严重的发病率，而且会导致严重的死亡率。由于消灭了天花，疫苗于1973年停止使用，使30岁以下的人得不到保护。此外，对免疫接种后保护持续时间的长短也有重大关切，因为老年人也可能容易感染和患病。令人惊讶的是，尽管开发了有效的天花病毒疫苗，但在我们对这种病毒与宿主免疫反应的相互作用的基本理解中仍存在许多问题。我们已经建立了牛痘病毒呼吸道感染模型，牛痘病毒是天花疫苗中使用的密切相关的病毒。本应用研究的一个优点是，它们侧重于鼻内感染后的免疫反应，这是获得天花病毒的自然途径，也是生物恐怖主义剂接种的可能途径。本应用程序中的研究建立在我们发表的新观察的基础上，即与接受低100倍病毒的小鼠相比，经鼻感染高剂量牛痘病毒的小鼠的CD8+T细胞反应严重降低。本文提出的研究目标是确定导致T细胞反应降低的机制。在目的1中，我们将确定高剂量感染后反应降低是细胞激活/扩增效率低下的结果，还是CD8+ T细胞的反应诱导了能量和/或凋亡。目的二抗原呈递细胞对CD8+T细胞在高剂量感染后减少反应的贡献将被评估。这些研究结果将为呼吸道感染后免疫反应的负调控提供新的重要信息，并可能导致开发新的治疗方法，可用于增强呼吸道病毒感染后的免疫反应。

DESCRIPTION (provided by applicant): There is an emerging threat of the use of respiratory pathogens as weapons of bioterrorism. Thus it is imperative that we understand the interaction of viral pathogens with the immune response in the specialized microenvironment of the lung. Although a number of pathogens pose a threat, of particular concern is variola virus. Infection with variola virus results not only in significant morbidity, but in significant fatality. As a result of the eradication of smallpox, the vaccine was discontinued in 1973, leaving those under the age of 30 unprotected. In addition there is significant concern regarding the length of time protection is sustained following immunization, such that older individuals are also likely to be susceptible to infection and disease. Surprisingly in spite of the development of an effective vaccine for variola virus, many questions remain in our basic understanding of the interaction of this virus with the host immune response. We have developed a model for respiratory infection with vaccinia virus, the closely related virus used in the vaccine against smallpox. An advantage of the studies in this application is that they focus on the immune response following intranasal infection, the natural route by which variola virus is obtained and a likely route of inoculation for agents of bioterrorism. The studies in this application build on our published novel observation that the CD8+T cell response following intranasal infection of mice with a high dose of vaccinia virus is severely decreased compared to mice receiving 100-fold less virus. The goal of the studies proposed herein is the identification of the mechanism(s) responsible for the decreased T cell response. In aim 1 we will determine whether the reduced response following high dose infection is the result of the inefficient activation/expansion of cells or whether anergy and/or apoptosis is induced in responding CD8+ T cells. In aim two the contribution of antigen presenting cells to the reduced CD8+T cell response observed following high dose infection will be evaluated. The results from these studies will provide new and important information on the negative regulation of the immune response following respiratory infection and may lead to the development of novel therapeutics that can be used to boost the immune response following respiratory infection with viruses.