The avian interferon system and its evasion by Avipoxviruses

干扰素系统在人体对病原体，特别是病毒的内在（先天）免疫中起着重要作用。先天免疫系统是在更原始的生物体中发现的古老机制的后代。它代表了一套广泛的非特异性防御，其工作是排斥病原体，或者至少在宿主的获得性免疫系统能够对以前见过的病原体做出快速反应之前，或者对以前没有见过的病原体做出较慢的反应之前，控制住病原体。干扰素系统也有助于启动和协调最初的获得性免疫反应。干扰素系统的重要性和有效性在最近10到12年才变得明显，病原体本身就是最好的证明。所有这些都进化出了对抗干扰素系统的机制，通常是多种机制，防止干扰素系统被启动（“诱导”）、放大和执行。在病毒的整个家族树中，部署了广泛而多样的病毒反防御措施，包括干扰素“调节剂”的活性。干扰素最早是1957年由艾萨克斯和林德曼在鸡细胞中发现的，但从那时起，我们对鸟类系统的了解就落后于对哺乳动物系统的了解。例如，鸡的第一个IFN序列是在1994年才确定的，比第一个哺乳动物的序列晚了14年。这同样阻碍了我们调查和理解病毒逃避禽干扰素反应的机制的能力。对于研究禽类先天反应和禽类病毒的科学家来说，存在着“第22条军规”的情况。如果没有表征禽流感系统的工具，就很难识别该系统的病毒调节剂，而如果没有调节剂，科学家就无法利用一些最有用的工具来探测宿主的完整系统。我们之前在“抗击牲畜病毒性疾病倡议”下获得的一笔联合赠款证明是帮助打破这一恶性循环的重要途径。在一项为期三年的资助中，不可能完全描述鸟类干扰素系统的所有组成部分，但该研究确实证实，正如预期的那样，鸟类系统与哺乳动物系统在实质上是相同的。然而，它也揭示了重要的和不可预测的差异，这很可能对病原体与鸟类宿主相互作用的方式产生重要影响。这在疫苗接种方面具有重要意义，疫苗接种已在世界范围内的家禽业广泛实施。不用说，鸟类和哺乳动物系统之间的显著差异可能对禽流感（H5N1禽流感）和西尼罗河病毒等新出现的人畜共患病病原体的倾向产生重要影响。同时，该项目提供了基本的工具来研究代表性禽病毒病原体对禽类干扰素反应的诱导和调节，甚至有助于从一种复杂的禽类病原体FWPV（一种痘病毒，以在哺乳动物中部署多种干扰素调节剂而闻名）中鉴定和初步表征新型干扰素调节剂。本提案旨在以两种方式建立这一广泛的概述。首先，它的目的是集中在禽类和哺乳动物宿主的干扰素系统之间确定的特殊显著差异，并澄清对宿主和病原体的后果。要做到这一点，有必要了解禽干扰素系统如何在这些关键区域发挥作用，并确定新型病毒调节剂如何发挥作用。要确定病毒调节剂是否只针对禽类方面，或者它们是否具有更广泛的特异性，将需要明确和详细地描述宿主和病毒机制。因此，虽然这两个目标是相当不同的，但它们是相互交织、相互作用和相互依存的。

The interferon system plays a major role in the body's inbuilt (innate) immunity to pathogens, particularly to viruses. The innate immune system is the descendant of ancient mechanisms found in more primitive organisms. It represents a broad set of non-specific defenses, the job of which is to repel the pathogen, or at least hold it in check until the host's acquired immune system can mount a quick response to pathogens it has seen before, or a slower response to those it has not. The interferon system also helps initiate and coordinate the initial acquired immune response. The importance and effectiveness of the interferon system has only become apparent in the last 10 to 12 years, and is best demonstrated by the pathogens themselves. All have evolved mechanisms, often multiple, to counteract the interferon system, preventing it being initiated ('induced'), amplified and executed. Across the family tree of viruses, a wide and diverse range of virus counter-defenses are deployed, involving the activity of interferon 'modulators'. Interferon was first discovered in chicken cells by Isaacs & Lindemann in 1957 but, since then, our knowledge of the avian system has lagged behind that of the mammalian system. For instance the first chicken IFN sequence was determined only in 1994, 14 years after the first mammalian sequence. This has equally hampered our ability to investigate and understand the mechanisms by which viruses evade the avian IFN responses. For scientists studying avian innate responses and avian viruses, a 'catch-22' situation has existed. Without the tools to characterise the avian system, it has been extremely difficult to identify virus modulators of the system and, without the modulators, scientists have been denied some of the most useful tools for probing the intact system of the host. A previous joint grant awarded to us under the Combating Viral Diseases of Livestock Initiative proved an important way of helping to break this vicious circle. It was not possible to fully characterise all the components of the avian interferon system in one three-year grant but the study did confirm that the avian system, as expected, was substantially the same as the mammalian system(s). However, it also revealed important and unpredictable differences, which could well have important implications for the way that pathogens interact with avian hosts. This has important implications in terms of vaccination, which is widely practised in the worldwide poultry industry. It also goes without saying that significant differences between avian and mammalian systems could have important consequences for the tropism of emerging zoonotic agents, such as Avian influenza (Bird Flu H5N1) and West Nile virus. At the same time the project provided basic tools to study the induction and modulation of the avian interferon response by representative avian viral pathogens and even to facilitate the identification and preliminary characterisation of novel interferon modulators from one complex avian pathogen, FWPV (a poxvirus - a family well known for deploying a wide range of interferon modulators in mammals). This proposal aims to build on that broad overview in two ways. Firstly it aims to focus on particular significant differences identified between the interferon systems of avian and mammalian hosts, and to clarify the consequences for both host and pathogens. To accomplish this it will be necessary to both understand how the avian interferon system functions in these key areas, and to identify how the novel viral modulators function. To identify whether the viral modulators target uniquely avian aspects, or whether they are broader in their specificity, will require clear and detailed characterisation of both host and viral mechanisms. Thus, although the two aims are fairly distinct, they are interwoven, interactive and interdependent.