Oligodeoxynucleotides containing CpG motifs (CpG-ODN) as an innate immune stimulator in broiler chickens

含有 CpG 基序的寡脱氧核苷酸 (CpG-ODN) 作为肉鸡先天免疫刺激剂

• 批准号: RGPIN-2018-06502
• 负责人: Gomis, Susantha
• 金额: $ 3.06万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=652131
• 关键词: Oligodeoxynucleotides; containing; CpG; motifs; ODN

Oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) activate immune cells and induce cytokine secretion. CpG-ODN has immense therapeutic potential in animal and human health and is a promising alternative to antibiotic use in the poultry industry, helping prevent the emergence of antibiotic-resistant superbugs. We reported for the first time that CpG-ODN alone can provide protective immunity against bacterial infections without vaccines or antibiotics. However, the mechanisms for such innate immune protection remains elusive. Studies are needed to understand the factors that orchestrate CpG-ODN regulated training of innate immunity leading to the host defense against pathogens. Several recent studies in mice and humans demonstrated an intricate link between metabolism and the immune system. Immune-metabolic interaction studies demonstrated the crucial roles of metabolic reprogramming in immune cell differentiation, proliferation, and function. Metabolic signature molecules have been discovered to predict the outcomes of immunity or diseases. Recently, using ultra-high pressure liquid chromatography-mass spectroscopy, we profiled metabolites in the serum and organs of CpG-ODN or saline-treated chickens. Interestingly, we found that CpG-ODN treatment significantly changes the metabolic profiles, increasing the molecules implicated in enhanced immune cell function, as in mice and humans. We hypothesize that immune-metabolic interaction plays a significant role in CpG-ODN-mediated protection in chickens. The short term objectives of the proposed research program will identify a holistic view of CpG-ODN-mediated protective immunity, by investigating the events occurring in various immune compartments and the ensuing cellular metabolic processes. Cellular activation and differentiation of immune cells, including dendritic cells, macrophages, T-cells, and cytokine-chemokine profiles, will be studied in different immune compartments. Immune cells will be sorted based on immune activation markers and costimulatory molecules for RNA sequencing analysis in conjunction with immune function, metabolomics, and cellular metabolic assays. These strategies will not only dissect the CpG-ODN-mediated immune protective mechanisms but will also be crucial for identifying whether the innate immune memory phenomenon, as reported in mice and humans, also exists in chickens. Our long-term goal is to optimize the use of CpG-ODN as an alternative to antibiotics in the poultry industry to ensure safe poultry products for consumers. This novel, innovative research will provide much basic information on the mechanisms of CpG-ODN-mediated immune protection in chickens. This program has great scope for HQP training in cutting-edge research, and the data generated will have a huge impact on the CpG-ODN research field for veterinary and human applications.

含有未甲基化CpG基序的寡脱氧核苷酸（CpG-ODN）激活免疫细胞并诱导细胞因子分泌。CpG-ODN在动物和人类健康方面具有巨大的治疗潜力，是家禽业中抗生素使用的一种有前途的替代品，有助于防止耐药性超级细菌的出现。我们首次报道了单独的CpG-ODN可以在没有疫苗或抗生素的情况下提供针对细菌感染的保护性免疫。然而，这种先天免疫保护的机制仍然难以捉摸。需要研究来了解协调CpG-ODN调节的先天免疫训练导致宿主防御病原体的因素。 最近对小鼠和人类的几项研究表明，新陈代谢和免疫系统之间存在着错综复杂的联系。免疫-代谢相互作用研究表明代谢重编程在免疫细胞分化、增殖和功能中的关键作用。已经发现代谢特征分子可以预测免疫或疾病的结果。最近，使用超高压液相色谱-质谱，我们分析了CpG-ODN或盐水处理的鸡的血清和器官中的代谢产物。有趣的是，我们发现CpG-ODN治疗显著改变了代谢谱，增加了与增强免疫细胞功能有关的分子，如在小鼠和人类中。我们推测免疫-代谢相互作用在CpG-ODN介导的鸡保护中起重要作用。拟议的研究计划的短期目标将确定CpG-ODN介导的保护性免疫的整体观点，通过调查发生在各种免疫区室的事件和随后的细胞代谢过程。将在不同的免疫区室中研究免疫细胞的细胞活化和分化，包括树突状细胞、巨噬细胞、T细胞和趋化因子谱。将基于免疫活化标志物和共刺激分子分选免疫细胞，用于RNA测序分析以及免疫功能、代谢组学和细胞代谢测定。这些策略不仅将剖析CpG-ODN介导的免疫保护机制，而且对于确定小鼠和人类中报道的先天免疫记忆现象是否也存在于鸡中也至关重要。我们的长期目标是优化CpG-ODN在家禽业中作为抗生素替代品的使用，以确保消费者获得安全的家禽产品。这项新的、创新的研究将为CpG-ODN介导的鸡免疫保护机制提供更多的基础信息。该计划在尖端研究方面为HQP培训提供了很大的空间，所产生的数据将对CpG-ODN研究领域的兽医和人类应用产生巨大影响。