Investigating Mechanisms and Genes that Shape Bovine Host Defence and Impact Disease Outcome in High and Low Immune Responders Phenotypes

研究塑造牛宿主防御和影响高和低免疫反应表型疾病结果的机制和基因

• 批准号: RGPIN-2016-03821
• 负责人: Mallard, Bonnie
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614654
• 关键词: Investigating; Mechanisms; Genes; Shape; Bovine

Emerging and re-emerging diseases of livestock, as well as antibiotic resistance are a major problem affecting animal and human health. This research program addresses various aspects of genetic regulation of the immune system as a means to better understand disease resistance of food-producing animals. The immune system is composed of genetically regulated cells and molecules with specialized ability to control response to infectious disease. Understanding the biological, genetic and epigenetic relationships within the immune system can facilitate identification of individuals with superior immune response (IR) and enhanced disease resistance. To that end, we have devised the first patented system to identify dairy cattle with elevated inherent IR, particularly during production when disease incidence is high and IR impaired. With our ability to identify high (H), low (L) and average (A) immune responders, it is now possible to exam in detail the genes, molecules and pathways that shape these diverse phenotypes. For example, antibody (AMIR) and cell-mediated immune response (CMIR) to type 1 and 2 test antigens indicates that dairy cattle and their offspring can be ranked based on H or L-IR and that this response is highly heritable (h2~25%). Noteworthy is that broad-based disease resistance is dependent on both AMIR and CMIR. Aspects of the innate immune system that initiate adaptive immunity also differ between individuals with these unique IR phenotypes, but need to be studied in more depth. The immune system is unique in that it has the ability to adapt host response to control a wide range of diverse pathogens. Selective breeding, simultaneously for AMIR and CMIR, based on estimated breeding values (EBVs) has been demonstrated by our group to improve a range of innate and adaptive defense mechanisms, as well as to improve overall animal health. However, we still know little about the genes, genetic pathways, or epigenetic influences that control H, L, or A immune responses. Information about the specific immunological mechanisms associated with each of these phenotypes is also scant. The core hypotheses for this research program are: 1 - Dairy cattle with H, A and L-IR phenotypes (based on EBVs) differ in the nature (eg quality) and expression (eg quantity) of key immune response genes and molecules. 2- Individuals classified as H, A or L immune responders will differ not only in their gene expression profiles but also in epigenetic marks on key immune response genes. This combined genetic and biological research program provides an original and innovative approach to study the basis of immunity in food-producing dairy cattle. The H and L-IR phenotypes are a powerful discovery method to uncover the various factors which have bovine immunity, improving animal health and food quality.

新出现和重新出现的牲畜疾病以及抗生素耐药性是影响动物和人类健康的主要问题。该研究计划涉及免疫系统遗传调控的各个方面，以更好地了解食品生产动物的抗病能力。免疫系统是由基因调控的细胞和分子组成，具有控制对感染性疾病反应的专门能力。了解免疫系统内的生物学、遗传学和表观遗传学关系可以有助于鉴定具有上级免疫应答（IR）和增强的抗病性的个体。为此，我们设计了第一个专利系统来识别固有IR升高的奶牛，特别是在疾病发生率高且IR受损的生产过程中。随着我们识别高（H），低（L）和平均（A）免疫应答者的能力，现在可以详细检查塑造这些不同表型的基因，分子和途径。例如，对1型和2型试验抗原的抗体（AMIR）和细胞介导的免疫应答（CMIR）表明，奶牛及其后代可以根据H或L-IR进行排序，并且这种应答具有高度遗传性（h2~25%）。值得注意的是，广泛的抗病性依赖于AMIR和CMIR。先天免疫系统启动适应性免疫的方面也不同的个体与这些独特的IR表型，但需要进行更深入的研究。 免疫系统是独特的，因为它有能力适应宿主反应，以控制各种各样的病原体。基于估计育种值（EBVs）同时对AMIR和CMIR进行选择性育种，已经被我们的小组证明可以改善一系列先天和适应性防御机制，以及改善整体动物健康。然而，我们仍然对控制H，L或A免疫反应的基因，遗传途径或表观遗传影响知之甚少。与这些表型中的每一种相关的特定免疫机制的信息也很少。 本研究计划的核心假设是： 1 -具有H、A和L-IR表型（基于EBV）的奶牛在关键免疫应答基因和分子的性质（例如质量）和表达（例如数量）上不同。 2-被分类为H、A或L免疫应答者的个体不仅在其基因表达谱上不同，而且在关键免疫应答基因上的表观遗传标记上也不同。 这种遗传学和生物学相结合的研究计划提供了一种原创和创新的方法来研究食品生产奶牛的免疫基础。H-IR和L-IR表型是揭示牛免疫力的各种因素，改善动物健康和食品质量的有力发现方法。