Control of T cell response during respiratory infection

呼吸道感染期间 T 细胞反应的控制

基本信息

批准号：
6674905
负责人：
Martha Ann Alexander-Miller
金额：
$ 25.2万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-15 至 2004-06-30
项目状态：
已结题

项目摘要

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.

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，我们必须了解病毒病原体与肺部特殊微环境中免疫反应的相互作用。尽管许多病原体构成威胁，但特别令人担忧的是天花病毒。天花病毒感染不仅导致显着的发病率，而且导致显着的死亡率。由于天花被消灭，疫苗于 1973 年停止使用，使 30 岁以下的人得不到保护。此外，人们对免疫接种后保护持续时间的长短也存在重大担忧，因此老年人也可能容易受到感染和疾病。令人惊讶的是，尽管开发出了针对天花病毒的有效疫苗，但我们对该病毒与宿主免疫反应相互作用的基本理解仍然存在许多问题。我们开发了一种牛痘病毒呼吸道感染模型，牛痘病毒与天花疫苗中使用的病毒密切相关。本申请研究的一个优点是，它们关注鼻内感染后的免疫反应、获得天花病毒的自然途径以及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，即与接受少 100 倍病毒的小鼠相比，鼻内感染高剂量牛痘病毒的小鼠后 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 细胞反应减弱的机制。在目标 1 中，我们将确定高剂量感染后反应减弱是否是细胞活化/扩增效率低下的结果，或者是否在响应的 CD8+ T 细胞中诱导了无反应性和/或凋亡。在目标二中，将评估抗原呈递细胞对高剂量感染后观察到的 CD8+T 细胞反应减少的贡献。这些研究的结果将为呼吸道感染后免疫反应的负调节提供新的重要信息，并可能导致开发出可用于增强呼吸道病毒感染后免疫反应的新型疗法。