Mechanisms for NK Cell Activation in Vaccinia Virus Control

痘苗病毒控制中 NK 细胞的激活机制

• 批准号: 8061621
• 负责人: Yiping Yang
• 金额: $ 57.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061621
• 关键词: Activated Natural Killer Cell; Antigen-Presenting Cells; CD8B1 gene; Cell physiology; Defense Mechanisms; Dendritic Cells; Development; Human; Immune; Immune system; In Vitro; Incidence; Infection; Lead; Life; Ligands; Mediating; NK Cell Activation; Natural Killer Cells; Pathway interactions; Play; Poxviridae; Principal Investigator; Role; Severe Adverse Event; Signal Pathway; Signal Transduction; Site; Smallpox; Smallpox Vaccine; T cell response; Testing; Toll-Like Receptor 2; Vaccination; Vaccines; Vaccinia virus; Virus Diseases; Work; Yang; design; in vivo; insight; novel strategies; response; success; trafficking

DESCRIPTION (provided by applicant): Vaccinia virus (VV) is the live smallpox vaccine responsible for the successful eradication of smallpox worldwide. This unparalleled success is now being threatened by bioterrorists reintroducing smallpox, against which vaccination is no longer routine. The revival of smallpox vaccination has been countermanded by relatively high incidence of severe adverse events associated with the currently used live VV vaccine. Thus, there is an imminent need to develop alternative and safe approaches to control not only the actual smallpox infection, but also potential complications from the smallpox vaccination. Critical for the development of effective strategies for the control of poxviral infections is to better understand the host's innate immune defense mechanism(s) against poxviruses in vivo. Natural killer (NK) cells represent an important component of the innate immune system and play a critical role in the control of poxviruses in vivo. However, how NK cells are activated in response to poxviral infection and the underlying mechanism(s) responsible for NK cell-mediated control of poxviruses remain largely undefined. We have shown that innate immune recognition of VV is mediated by Toll-like receptor 2 (TLR2) and that activation of the TLR2-MyD88 pathway is crucial to the control of VV in vivo. In the preliminary studies, we have further demonstrated that the TLR2-MyD88 pathway is required for the activation of NK cells upon W infection and their trafficking to the site of infection in vivo, and that stimulation of the TLR2 pathway by W directly on NK cells, but not on accessory cells such as dendritic cells (DCs), is necessary for NK cell activation in vitro. Taken together, these observations suggest a central hypothesis that direct stimulation of the TLR2-MyD88 pathway on NK cells by W is required for NK cell activation, recruitment and function in the control of W in vivo. To test this hypothesis, we will pursue the following five aims: 1) To define the role of direct TLR2 signaling in NK cell activation, trafficking, and function in vivo; 2) To determine the mechanisms underlying TLR2-dependent NK cell activation and trafficking upon VV infection; 3) To identify the W ligand(s) that triggers the TLR2 signaling pathway; 4) To investigate the role of TLR2-dependent NK cell activation in adaptive CD8+ T cell response to W infection; and 5) To study the role of the TLR2 pathway in the activation of human NK cells by VV. We expect this work will lead to a better understanding of mechanisms underlying NK cell activation, trafficking and function in response to VV infection in vivo, which in turn will provide important insights into the design; of novel strategies to effectively activate NK cell function for the control of poxviral infections.

描述（由申请人提供）：Vaccinia病毒（VV）是负责成功消除全球天花的活天花疫苗。现在，这种无与伦比的成功正受到重新引入天金的生物恐怖主义的威胁，这不再是常规的。与当前使用的活VV疫苗相关的严重不良事件的发生率相对较高的发生率，天花疫苗接种的复兴已得到反合。因此，迫在眉睫的需要开发替代和安全的方法来不仅控制实际的天花感染，而且还需要从天花疫苗接种的潜在并发症。对控制痘病毒感染的有效策略的制定至关重要的是，要更好地了解宿主对体内痘病毒的先天免疫防御机制。天然杀手（NK）细胞代表了先天免疫系统的重要组成部分，并在体内控制痘病毒中起关键作用。但是，如何响应蛇毒感染而激活NK细胞以及负责NK细胞介导的痘病毒控制的基本机制仍然很大程度上不确定。我们已经表明，VV的先天免疫识别是由Toll样受体2（TLR2）介导的，并且TLR2-MYD88途径的激活对于控制VV的体内VV至关重要。在初步研究中，我们进一步证明了TLR2-MYD88途径在W感染后激活NK细胞及其在体内的感染部位的运输，而W直接在NK细胞上刺激W在NK细胞上，而不是辅助细胞（如dccs）（dcs）的刺激。综上所述，这些观察结果表明了一个中心假设，即通过W对NK细胞对NK细胞的TLR2-MYD88途径进行直接刺激是NK细胞激活，募集和功能在W WIVO中控制W的情况下。为了检验这一假设，我们将追求以下五个目的：1）定义直接TLR2信号传导在NK细胞激活，运输和体内功能中的作用； 2）确定TLR2依赖性NK细胞激活和VV感染后运输的机制； 3）确定触发TLR2信号通路的W配体； 4）研究TLR2依赖性NK细胞活化在自适应CD8+ T细胞对W感染的反应中的作用；和5）研究TLR2途径在VV通过人NK细胞激活中的作用。我们预计这项工作将使人们对NK细胞激活，运输和功能的基础机制有更好的了解，以响应体内VV感染，这反过来又将为设计提供重要的见解。有效激活NK细胞功能的新型策略来控制蛇毒感染。