The avian interferon system and its evasion by Avipoxviruses

禽干扰素系统及其对禽痘病毒的逃避

• 批准号: BB/G018545/1
• 负责人: Michael Skinner
• 金额: $ 49.47万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG018545%2F1
• 关键词: avian; interferon; system; its; evasion

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.

干扰素系统在机体对病原体，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。它代表了一系列广泛的非特异性防御，其工作是击退病原体，或者至少控制它，直到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，或者对以前没有见过的病原体做出较慢的反应。干扰素系统还有助于启动和协调最初的获得性免疫应答。干扰素系统的重要性和有效性只是在过去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机制，通常是多重的，以抵消干扰素系统，防止它被启动（“诱导”），放大和执行。在整个病毒家族树中，部署了广泛而多样的病毒反防御，涉及干扰素“调节剂”的活性。1957年，Isaacs和Lindemann首次在鸡细胞中发现了干扰素，但从那时起，我们对鸟类系统的了解就落后于哺乳动物系统。例如，第一个鸡IFN序列仅在1994年确定，比第一个哺乳动物序列晚了14年。这同样阻碍了我们调查和理解病毒逃避禽类IFN应答的机制的能力。对于研究鸟类先天反应和鸟类病毒的科学家来说，存在着一种“第22条军规”的情况。如果没有工具来识别禽类系统，就很难识别该系统的病毒调节剂，如果没有调节剂，科学家们就无法获得一些最有用的工具来探测宿主的完整系统。根据“防治牲畜病毒性疾病倡议”向我们提供的先前联合赠款证明是帮助打破这一恶性循环的重要途径。在一个为期三年的资助项目中不可能完全涵盖禽类干扰素系统的所有组成部分，但该研究确实证实了禽类系统与预期的一样，与哺乳动物系统基本相同。然而，它也揭示了重要和不可预测的差异，这可能对病原体与鸟类宿主相互作用的方式产生重要影响。这对全世界家禽业广泛采用的疫苗接种具有重要意义。不用说，鸟类和哺乳动物系统之间的显著差异可能对新出现的人畜共患病病原体的嗜性产生重要影响，如禽流感（禽流感H5 N1）和西尼罗河病毒。与此同时，该项目提供了基本的工具来研究代表性禽类病毒病原体对禽类干扰素应答的诱导和调节，甚至有助于从一种复杂的禽类病原体FWPV（痘病毒-一个众所周知的在哺乳动物中部署广泛的干扰素调节剂的家族）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在这一广泛的概览基础上更进一步。首先，它的目的是集中在鸟类和哺乳动物宿主的干扰素系统之间的特别显着的差异，并澄清宿主和病原体的后果。为了实现这一点，将有必要了解如何在这些关键领域的鸟类干扰素系统的功能，并确定如何新的病毒调节剂的功能。为了确定病毒调节剂是否唯一靶向禽类方面，或者它们是否具有更广泛的特异性，将需要对宿主和病毒机制进行明确和详细的表征。因此，虽然这两个目标相当不同，但它们是相互交织、相互作用和相互依存的。

项目成果

Construction of FWPV Chimaeric MVA.

FWPV嵌合MVA的构建。

• DOI: 10.21769/bioprotoc.1376
• 发表时间: 2015
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Buttigieg KR

Chicken cGAS senses fowlpox virus infection and regulates macrophage effector functions

鸡cGAS感知鸡痘病毒感染并调节巨噬细胞效应功能

• DOI: 10.1101/2020.10.01.321422
• 发表时间: 2020
• 作者: Oliveira M

MOESM1 of Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-a)

鸡干扰素的 MOESM1：通过微阵列和 RNA-seq 鉴定鸡 I 型干扰素 (IFN-a) 处理的初级鸡胚成纤维细胞的禽干扰素刺激基因

• DOI: 10.6084/m9.figshare.c.3643613_d2
• 发表时间: 2016
• 作者: Giotis E

Chicken cGAS Senses Fowlpox Virus Infection and Regulates Macrophage Effector Functions.

• DOI: 10.3389/fimmu.2020.613079
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Oliveira M;Rodrigues DR;Guillory V;Kut E;Giotis ES;Skinner MA;Guabiraba R;Bryant CE;Ferguson BJ
• 通讯作者: Ferguson BJ