Control of T cell response during respiratory infection

描述（由申请人提供）：呼吸道病原体被用作生物恐怖主义武器的威胁正在出现。因此，我们有必要了解病毒病原体与肺部特殊微环境中免疫反应的相互作用。虽然许多病原体构成威胁，但特别令人关注的是天花病毒。天花病毒感染不仅导致显著的发病率，而且导致显著的死亡率。由于天花的根除，疫苗于1973年停止使用，使得30岁以下的人没有受到保护。此外，免疫后保护持续时间的长短也令人严重关切，因为老年人也可能容易感染和患病。令人惊讶的是，尽管已经开发出有效的天花病毒疫苗，但我们对这种病毒与宿主免疫反应相互作用的基本了解仍然存在许多问题。我们已经建立了牛痘病毒呼吸道感染的模型，牛痘病毒与天花疫苗中使用的病毒密切相关。本申请中的研究的优点在于，它们集中于鼻内感染后的免疫应答、获得天花病毒的天然途径和生物恐怖主义制剂的可能接种途径。本申请中的研究建立在我们发表的新观察结果的基础上，即与接受100倍以下病毒的小鼠相比，用高剂量牛痘病毒鼻内感染小鼠后的CD 8 +T细胞应答严重降低。本文提出的研究的目标是鉴定导致T细胞应答降低的机制。在目标1中，我们将确定高剂量感染后降低的应答是否是细胞的低效活化/扩增的结果，或者是否在应答的CD 8 + T细胞中诱导了无反应性和/或凋亡。在目的二中，将评价抗原呈递细胞对在高剂量感染后观察到的降低的CD 8 +T细胞应答的贡献。这些研究的结果将为呼吸道感染后免疫应答的负调节提供新的重要信息，并可能导致开发可用于增强病毒呼吸道感染后免疫应答的新型治疗方法。

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.