Nutritional regulation of genes associated with avian B cell receptors involved in innate and adaptive immunity

在家禽饲养中减少使用抗菌剂可以通过提高鸡的自然免疫力来实现，从而最大限度地减少疾病和病原体的脱落。对雏鸟卵内免疫系统的干预对雏鸟孵化后的免疫力有显著的影响，提高了其抵抗疾病挑战的能力。然而，不仅是雏鸟的免疫系统必须加强，成年鸟的免疫系统也是如此。蛋鸡的营养状况直接影响鸡蛋的营养成分，进而影响胚胎和雏鸡的发育和营养状况。这对基因表达的表观遗传调控有影响，允许分裂细胞记住或印记它们发育早期发生的信号事件。叶酸在核酸和蛋白质合成中起着关键作用；叶酸缺乏会显著改变免疫反应。我的假设是，在种鸡的日粮中添加叶酸将通过BCR和TCR基因甲基化状态影响B细胞前体的发育，从而促进B细胞在胚胎中的发育。在这项研究计划中，早期宿主先天与适应性免疫系统发育和成熟之间的相关性将被用来解释抗原受体(BCR和TLR)的表观遗传调节以及随着细胞成熟而产生的细胞因子。该计划将进一步将表观遗传学特征、B细胞发育和免疫评估与口服营养干预相结合，使用产生叶酸的益生菌作为表观遗传学修饰剂。本研究计划的主要目的是：(1)研究B细胞前体中与BCR细胞内信号蛋白Igü、MHC II和TLR-2和TLR-4基因相关的表观遗传学变化，并确定甲基化调控下的基因；(2)确定在V(D)J重组中以及在TLR-2和TLR4基因的预测启动子区中，甲基供体是否与DNA甲基化相关；(3)确定通过DNA甲基化进行的表观遗传编程是否调节基因的表达。这一研究结果不仅对家禽养殖业具有重要的实际应用价值，而且将有助于更好地理解DNA甲基化和去甲基化介导的染色质重塑如何通过BCR和TCR在调节V(D)J区重组和生殖系转录中发挥重要作用。这些信息将提高我们对B细胞在鸡胚胎中发育和成熟的理解，并将开发整合营养干预和表观免疫结果的模型。确定益生菌增强免疫反应的效果对加拿大家禽业的未来(营养和动物健康)至关重要，因为这将有助于确定哪个养殖阶段(蛋鸡、肉鸡等)。可能从营养干预策略中受益最大

Reducing the use of antimicrobials in the rearing of poultry can be achieved by enhancing the natural immunity of chickens, thus minimizing disease and pathogen shedding. Intervention of the immune system of the chick in ovo has a dramatic effect on the immunity of the bird post-hatch, increasing its ability to resist a disease challenge. However, it is not only the chick’s immune system that must be strengthened but also that of the adult bird. The nutritional status of the laying hen directly influences the nutrient composition of the egg and, in turn, the development and nutritional status of the embryo and hatchling. This has implications for epigenetic regulation of gene expression allowing dividing cells to memorize, or imprint, signalling events that occurred earlier in their development. Folate plays a critical role in nucleic acid and protein synthesis; a deficiency of folate significantly alters the immune response. My hypothesis is that the inclusion of folate in breeder hens’ diet will enhance B cell development in the embryo by influencing B cell precursor development through BCR and TCR gene methylation status. In this research program, correlation between early host innate and adaptive immune system development and maturation will be used to explain epigenetic regulation at the antigen receptors (BCR and TLR) and cytokine production as the cells mature. This program will furthermore integrate epigenetic characterization, B cell development, and immunity evaluation with oral nutrition intervention using folate-producing probiotics as epigenetic modifiers. The main objectives of this research program are to: (1) Study epigenetic changes associated with BCR intracellular signalling protein Igß, MHC II, and TLR-2 and TLR-4 genes in B cell precursors, and identify genes under methylation regulation; (2) Determine whether inclusion of methyl donor is correlated with DNA methylation in V(D)J recombination and in the predicted promoter region of TLR-2 and TLR4 genes; (3) Determine whether epigenetic programming via DNA methylation regulates gene expression. The outcome of this research will not only have important practical application for the poultry industry, but will also yield a better understanding of how chromatin remodelling mediated by DNA methylation and demethylation plays a major role in regulating V(D)J regions recombination and germ line transcription through the BCR and TCR. The information will improve our understanding of B cell development and maturation in chicken embryos, and will develop models integrating nutritional intervention and epigenetic immune outcome. Determining the effect of probiotics in boosting the immune response is critical to the future of the Canadian Poultry Industry (nutrition and animal health) as it will help determine which breeding stage (laying hens, broilers, etc.) may benefit the most from nutritional intervention strategies