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

新出现和再次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。这项研究计划涉及免疫系统遗传调节的各个方面，以此作为更好地了解食品类动物抗病能力的一种手段。免疫系统由受基因调控的细胞和分子组成，这些细胞和分子具有控制对传染病的反应的专门能力。了解免疫系统内的生物、遗传和表观遗传关系有助于识别具有优越免疫反应(IR)和增强抗病能力的个体。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，特别是在疾病发病率高和IR受损的生产期间。有了我们识别高(H)、低(L)和一般(A)免疫应答者的能力，现在有可能详细检查形成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)和细胞免疫反应(CMIR)表明，奶牛及其后代可以根据H或L-IR进行分级，这种反应具有很高的遗传性(H2~25%)。值得注意的是，广泛的抗病能力取决于AMIR和CMIR。启动适应性免疫的先天免疫系统在这些独特的IR表型的个体之间也不同，但需要更深入的研究。 免疫系统是独一无二的，因为它有能力适应宿主的反应，以控制广泛的不同病原体。我们小组已经证明，基于估计育种值(EBV)的选择性育种，同时用于AMIR和CMIR，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。与这些表型相关的特定免疫机制的信息也很少。 这项研究计划的核心假设是： 1-具有H、A和L-IR表型的奶牛(基于EBV)在关键免疫反应基因和分子的性质(如质量)和表达(如数量)上存在差异。 2-被归类为H、A或L免疫应答者的个体不仅基因表达谱不同，而且关键免疫应答基因的表观遗传标记也不同。 这一遗传和生物学相结合的研究计划为研究产粮奶牛的免疫基础提供了一种原创性和创新性的方法。H和L-IR表型是揭示影响牛免疫的各种因素，改善动物健康和食品品质的有力发现方法。

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.