Identification of genetic variation in innate immune response genes associated with resistance to chicken viral infections

鉴定与鸡病毒感染抵抗力相关的先天免疫反应基因的遗传变异

• 批准号: BB/D013704/1
• 负责人: David Burt
• 金额: $ 42.19万
• 依托单位: Roslin Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD013704%2F1
• 关键词: Identification; genetic; variation; innate; immune

The UK poultry industry faces increasing challenges in the 21st century. Many of the drugs used to control diseases in poultry are being withdrawn from use. At the same time, improving welfare standards mean that the industry is becoming more free-range. But the downside is that free-range chickens face higher rates of disease challenge, for example through contact with wild birds. One answer to this problem is to breed birds, which have a higher natural resistance to disease. To do this, we need to understand the bird's immunity to disease, so that we can identify ways to control that response. We already know that in birds and mammals, the immune response can be divided into two arms - the innate response and the adaptive response. The latter is a very specific response, which hopefully leads to immune 'memory', in other words the ability to respond rapidly to subsequent infections with the same pathogen. This is how vaccination works, however, it is specific to each pathogen the bird encounters, and thus would not give general resistance to disease. Our target is the innate immune response. This is a generalised response that recognises components of a wide range of pathogens, for example, specific types of molecules in a bacterial coat. It serves two roles - it limits infection until the adaptive immune response can kick in, and also provides signals that control the adaptive immune response. For many infections, a strong innate immune response is all that is needed to control the pathogen and prevent the onset of disease. Our initial aim in this project is to identify as many of the genes in the chicken as possible that are involved in the innate immune response. This is now possible since the chicken genome was sequenced last year and already almost 18,000 genes have been predicted. Our initial gene set will be determined by comparisons with similar gene sets in mammals, and what we can identify from the chicken genome sequence. The next step will be to identify which members of this predicted set of genes are actually involved in the innate immune response to infection with viruses. We will do this by infecting birds with different viruses and looking at the expression of genes following infection, on a global level using whole genome microarrays. These are glass slides containing short unique sequences corresponding to each known gene in the chicken genome that can be used to detect whether a gene is turned on or off. After complex mathematical analysis, one can examine global gene expression using these microarrays and identify which chicken genes respond to a particular viral infection. We have chickens lines, which we know differ in their resistance to viral infections. We suspect that at least some of that difference will be at the level of the innate immune response. Once we know which genes are involved in the innate response to viral infection, we will then look for sequence differences or polymorphisms between these chicken lines. We will be looking for changes at single nucleotides within the DNA sequence of these genes, known as SNPs (single nucleotide polymorphisms). We will then predict, and later test, if these SNPs are likely to make a functional difference to the protein encoded by the gene, either in its structure (for example by changing the amino acid sequence) or the level of its expression. Finally, we will then assess if individual SNPs track with resistance to viral infection using crosses between resistant and susceptible lines, in simplest terms by seeing if the SNP is always found in a resistant bird. These SNPs can then be used as selectable markers in normal breeding programmes to select birds that are naturally more resistant to viral infection. In addition, resistant poultry will represent a new tool in our defense against infectious disease in humans.

世纪英国家禽业面临着越来越多的挑战。许多用于控制家禽疾病的药物正在停止使用。与此同时，福利标准的提高意味着该行业正变得更加自由放养。但缺点是，自由放养的鸡面临更高的疾病挑战率，例如通过与野生鸟类接触。解决这个问题的一个办法是繁殖鸟类，因为鸟类对疾病有更高的天然抵抗力。要做到这一点，我们需要了解鸟类对疾病的免疫力，这样我们就可以找到控制这种反应的方法。我们已经知道，在鸟类和哺乳动物中，免疫反应可以分为两类-先天反应和适应性反应。后者是一种非常特异性的反应，有望导致免疫“记忆”，换句话说，能够对随后的相同病原体感染迅速作出反应。这就是疫苗接种的工作原理，然而，它对鸟类遇到的每种病原体都是特异性的，因此不会对疾病产生普遍的抵抗力。我们的目标是先天免疫反应。这是一种普遍的反应，可以识别各种病原体的成分，例如细菌外壳中的特定类型的分子。它有两个作用-它限制感染，直到适应性免疫反应可以启动，并提供控制适应性免疫反应的信号。对于许多感染，强大的先天免疫反应是控制病原体和预防疾病发作所需的全部。我们在这个项目中的最初目标是识别尽可能多的基因在鸡参与先天免疫反应。自从去年对鸡的基因组进行测序以来，这已经成为可能，并且已经预测了近18，000个基因。我们的初始基因集将通过与哺乳动物中类似基因集的比较以及我们可以从鸡基因组序列中识别出的内容来确定。下一步将是确定这组预测基因中的哪些成员实际上参与了对病毒感染的先天免疫反应。我们将用不同的病毒感染鸟类，并在全球范围内使用全基因组微阵列观察感染后的基因表达。这些载玻片含有与鸡基因组中每个已知基因相对应的短的独特序列，可用于检测基因是打开还是关闭。在复杂的数学分析之后，人们可以使用这些微阵列检查全局基因表达，并确定哪些鸡基因对特定的病毒感染做出反应。我们有鸡系，我们知道它们对病毒感染的抵抗力不同。我们怀疑，至少有一些差异将在先天免疫反应的水平上。一旦我们知道哪些基因参与了对病毒感染的先天反应，我们将寻找这些鸡系之间的序列差异或多态性。我们将在这些基因的DNA序列中寻找单核苷酸的变化，称为SNP（单核苷酸多态性）。然后，我们将预测并测试这些SNP是否可能对基因编码的蛋白质产生功能差异，无论是在结构上（例如通过改变氨基酸序列）还是在表达水平上。最后，我们将使用抗性和易感品系之间的杂交来评估单个SNP是否跟踪对病毒感染的抗性，简单地说，就是看看SNP是否总是在抗性鸟中发现。这些SNPs可以在正常的育种计划中用作选择标记，以选择天然对病毒感染更具抵抗力的鸟类。此外，耐药性家禽将成为我们防御人类传染病的新工具。

项目成果

Molecular immunophenotyping of lungs in naïve and vaccinated chickens early after pulmonary avian influenza A (H9N2) virus infection

甲型禽流感 (H9N2) 病毒感染后早期对未接种疫苗和接种疫苗的鸡进行肺部分子免疫表型分析

• DOI: 10.1016/j.vetimm.2008.10.245
• 发表时间: 2009
• 期刊: Veterinary Immunology and Immunopathology
• 影响因子: 1.8
• 作者: Degen W

Transcriptomic Profiling of Virus-Host Cell Interactions following Chicken Anaemia Virus (CAV) Infection in an In Vivo Model.

体内模型中鸡肉贫血病毒（CAV）感染后病毒宿主宿主相互作用的转录组分析。

• DOI: 10.1371/journal.pone.0134866
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Giotis ES;Rothwell L;Scott A;Hu T;Talbot R;Todd D;Burt DW;Glass EJ;Kaiser P
• 通讯作者: Kaiser P

Towards the selection of chickens resistant to Salmonella and Campylobacter infections.

选择对沙门氏菌和弯曲杆菌感染有抵抗力的鸡。

• 发表时间: 2009
• 期刊: Bulletin et memoires de l'Academie royale de medecine de Belgique
• 作者: Kaiser P

Evolution of avian innate immune system

禽类先天免疫系统的进化

• 发表时间: 2008
• 作者: Burt, D

Evolutionary analysis of the CSF1R and its ligands in vertebrates

脊椎动物 CSF1R 及其配体的进化分析

• 发表时间: 2011
• 作者: Gutowska, M.W.