Imaging Vaccina Viral-Host Pathogenesis

疫苗病毒宿主发病机制成像

• 批准号: 7091139
• 负责人: Gary D Luker
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091139
• 关键词: Poxviridae; Poxviridae disease; T lymphocyte; active immunization; immune response; immunity; infection; proteins; vaccinia virus

DESCRIPTION (provided by applicant): Project summary: Variola virus (smallpox) is regarded to be 1 of the most significant threats as a bioterrorism agent. Because smallpox was eradicated as a human disease before the molecular tools were available to dissect host immune responses, little is known about the molecular, cellular, and organismal characteristics of host immunity to poxvirus infection. The urgent scientific need for these studies is emphasized by a recent National Academy of Science project on smallpox, which stated that "it is important to define the innate immune response to a poxvirus infection, including ... cellular receptors involved in activation of elements of the innate immune system". Recent studies suggest that Toll-like receptors (TLR) may be 1 of the key cellular determinants of innate immunity to poxviruses. TLR are crucial for the host innate immune system to recognize and respond to invading pathogens, and TLR signaling also regulates the adaptive immune response. The objective of this research is to develop whole animal imaging techniques to study poxvirus pathogenesis in mouse models, enabling real-time studies of TLR effects on viral replication and host response in the context of a living animal. These imaging technologies will be used to accomplish these specific aims: 1) determine the extent to which TLR signaling through 2 different adaptor proteins (MyD88 and Trif) limits replication and systemic spread of vaccinia virus, the established model for poxvirus infection; and 2) establish effects of TLR signaling on distribution and trafficking of T lymphocytes to sites of vaccinia infection. This research will provide a detailed understanding of TLR in poxvirus pathogenesis, providing an essential foundation for developing strategies to control smallpox infection and its spread. Furthermore, our studies will establish innovative imaging approaches for studying poxvirus pathogenesis in living mice. These imaging strategies can be applied to other aspects of poxvirus- host pathogenesis and pre-clinical testing of new vaccination strategies or anti-viral compounds. Relevance: This research will establish functions of a specific family of molecules that likely are important in the immune response to vaccinia virus, the virus used as a model of smallpox. A key component of the application is validating imaging techniques to detect and analyze the virus and defined host immune cells in a living animal. Collectively, the research is expected to facilitate the development of improved vaccines and treatments for smallpox, thereby enhancing our ability to prevent the use of smallpox for bioterrorism.

描述（由申请人提供）： 项目摘要：天花病毒（天花）被认为是生物恐怖主义最重大的威胁之一。由于在分子工具可用于剖析宿主免疫反应之前，天花作为一种人类疾病已被根除，因此人们对痘病毒感染的宿主免疫的分子、细胞和有机体特征知之甚少。美国国家科学院最近的一项天花项目强调了这些研究的迫切科学需要，该项目指出“定义对痘病毒感染的先天免疫反应非常重要，包括……参与激活天花元素的细胞受体”先天免疫系统”。最近的研究表明，Toll 样受体 (TLR) 可能是痘病毒先天免疫的关键细胞决定因素之一。 TLR 对于宿主先天免疫系统识别和响应入侵病原体至关重要，并且 TLR 信号传导还调节适应性免疫反应。本研究的目的是开发整体动物成像技术来研究小鼠模型中的痘病毒发病机制，从而能够实时研究活体动物中 TLR 对病毒复制和宿主反应的影响。这些成像技术将用于实现以下具体目标：1) 确定 TLR 信号通过 2 种不同的接头蛋白（MyD88 和 Trif）限制痘苗病毒（已建立的痘病毒感染模型）复制和全身传播的程度； 2) 确定 TLR 信号传导对 T 淋巴细胞分布和运输到牛痘感染部位的影响。这项研究将详细了解痘病毒发病机制中的 TLR，为制定控制天花感染及其传播的策略提供重要基础。此外，我们的研究将建立创新的成像方法来研究活体小鼠痘病毒的发病机制。这些成像策略可应用于痘病毒宿主发病机制的其他方面以及新疫苗接种策略或抗病毒化合物的临床前测试。相关性：这项研究将确定一个特定分子家族的功能，这些分子可能对牛痘病毒（该病毒用作天花模型）的免疫反应很重要。该应用程序的一个关键组成部分是验证成像技术来检测和分析活体动物中的病毒和确定的宿主免疫细胞。总的来说，这项研究预计将促进改进天花疫苗和治疗方法的开发，从而增强我们防止利用天花进行生物恐怖主义的能力。