Understanding how viral innate immune evasion strategies affect adaptive immunity, and the application to vaccine development

疫苗是预防感染和疾病传播的最佳手段之一。尽管现有60多种疫苗，但仍需要针对艾滋病毒、疟疾和登革热等感染的疫苗，这些感染对全球卫生构成巨大负担。造成这一问题的原因是我们对提供最佳保护的免疫反应的类型以及疫苗接种如何最好地引起这一类型的理解不够全面。在这项研究中，用于根除天花的疫苗--痘苗病毒(VACV)将被用作一个模型，以提高目前对疫苗接种免疫反应的理解，并将利用这些信息设计更有效的疫苗。有两只手臂组成了我们的免疫系统。第一种是“先天”免疫系统，它对感染反应迅速，但不是病原体特异性的。先天免疫有助于控制感染，同时发展“适应性”免疫反应。获得性免疫是针对入侵病原体的，是彻底清除病原体所必需的。重要的是，适应性免疫反应作为一种长期的记忆免疫来保护免受后续感染。正是这种长期的、病原体特异性记忆免疫的发展为疫苗接种提供了基础。先天免疫反应在成功接种疫苗中的重要性正变得越来越清楚，尽管它如何促进记忆免疫还不是很清楚。人体内的细胞能够检测到入侵微生物的存在，并通过产生细胞因子和干扰素等分子来做出反应--因此它们被称为“干扰”病毒感染。除了限制病毒复制，这些特殊的蛋白质还将白细胞(白细胞)吸引到感染部位，以便它们可以杀死病原体感染的细胞，并刺激控制适应性免疫反应的白细胞的激活。病毒有限制这些抗致病和免疫激活分子的产生和作用的反措施，而VACV有许多机制来实现这一点。我们实验室的工作已经证明，通过改造VACV来去除其蛋白产物限制先天免疫反应的基因，如细胞因子和干扰素，可以提高VACV作为疫苗的效力。这些数据很有价值，因为它们强调了先天免疫在塑造和影响记忆免疫反应方面的重要性。我们要回答的问题是，从VACV中移除这些先天免疫抑制基因对记忆免疫有何积极影响？通过回答这个问题，我们不仅能够提高VACV的疫苗潜力，还将加强目前对先天免疫系统如何塑造记忆免疫反应的理解，这些信息可用于设计更好的疫苗。VACV是回答这个问题的一个很好的模型，因为它是一种研究得很好的病毒，已经有许多工具可用，它已经被成功地用作根除天花的疫苗，并且有一个强大的VACV感染和疫苗接种的小鼠模型。此外，VACV是一种流行的候选载体，用于预防其他疾病，如艾滋病毒和疟疾，因此这项拟议研究产生的数据可以直接用于提高这种病毒的疫苗潜力。

Vaccines are one of the best means to prevent infection and the spread of disease. Although more than 60 vaccines exist, vaccines are still needed against infections such as HIV, malaria and dengue that comprise a huge burden on global health. Contributing to this problem is our incomplete understanding of the type of immune response that provides optimal protection and how this is best evoked by vaccination. In this study vaccinia virus (VACV), the vaccine used to eradicate smallpox, will be used as a model to improve current understanding of the immune response to vaccination and this information will be used to design more potent vaccines. There are two arms that make up our immune system. The first is the 'innate' immune system, which is quick to respond to infection but is not pathogen specific. Innate immunity helps to control the infection whilst the 'adaptive' immune response develops. Adaptive immunity is specific to the invading pathogen and is required for complete pathogen clearance. Importantly, the adaptive immune response endures as a long-lived memory immunity that protects from subsequent infection. It is the development of this long-lived, pathogen-specific memory immunity that provides the basis for vaccination. The importance of the innate immune response in successful vaccination is becoming clear, although exactly how it contributes to memory immunity is not well understood. Cells in the body are able to detect the presence of invading microorganisms and respond by producing molecules such as cytokines and interferons - so named as they 'interfere' with viral infection. As well as limiting virus replication, these specialised proteins attract white blood cells (leukocytes) to the site of infection so that they can kill pathogen-infected cells and stimulate the activation of leukocytes that control the adaptive immune response. Viruses have counter-measures that limit the production and action of these anti-pathogenic and immune-activating molecules and VACV has numerous mechanisms to achieve this. Work in our laboratory has demonstrated that engineering VACV to remove the genes whose protein products act to limit the innate immune response, such as cytokines and interferons, can improve the potency of VACV as a vaccine. These data are valuable because they highlight the importance of innate immunity in shaping and influencing the memory immune response. The question we aim to answer is how does the removal of these innate immune inhibitory genes from VACV positively impact on memory immunity? By answering this question we will not only be able to improve the vaccine potential of VACV, but also enhance current understanding of how the innate immune system shapes memory immune responses, information that can be used to design better vaccines in general. VACV is a good model to answer this question as it is a well-studied virus where numerous tools are already available, it has already been used as a successful vaccine for the eradication of smallpox and there is a robust mouse model of VACV infection and vaccination. Furthermore VACV is a popular candidate as a vector for the vaccination against other diseases, such as HIV and malaria, thus the data generated by this proposed study can be directly used to improve the vaccine potential of this virus.