The impact of gut microbiome on the innate immune response against enteric coronaviruses

肠道微生物组对肠道冠状病毒先天免疫反应的影响

• 批准号: BB/W009870/1
• 负责人: Amanda Warr
• 金额: $ 51.8万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW009870%2F1
• 关键词: impact; gut; microbiome; innate; immune

Coronaviruses emerge relatively often in pigs, and most commonly cause severe enteric disease in young pigs. Enteric diseases that cause diarrhea in young pigs impact their welfare and are a major source of loss to farmers as there is a high rate of mortality, and those that survive often have reduced growth for the duration of disease and recovery. Often farmers treat young pigs with antibiotics to protect them from bacteria that can cause diarrhea, however this does not protect them from non-bacterial sources of enteric disease, such as viruses, or from disease caused by antibiotic resistant bacteria. There is evidence that commensal microbes that inhabit the guts of animals, the gut microbiome, play a role in priming the immune system to more quickly and efficiently respond to pathogens. Young pigs lack a mature gut microbiome, and treating them with antibiotics further depletes their microbiomes. Given the microbiome's role in priming the immune system to respond to pathogens, introducing microbes that are capable of priming the immune system prior to exposure to pathogens could lead to a more robust immune response to these pathogens and lead to a milder disease, or no disease, as is seen in adult pigs.I will manipulate the microbiomes of pigs to change the diversity of species present in the gut prior to challenging with Transmissible Gastroenteritis Virus (TGEV). The pigs will be cannulated to allow for access to their ileum microbiome throughout the trial. I will use cutting edge technology to understand how the introduced microbes change the gut microbiome and the pigs' immune responses, and I will identify functional potential in the microbiome that may contribute to changes in the immune response. I will test candidate bacteria in cells and pig organoids to identify bacteria that trigger changes in homeostatic immune signalling and that impact the response to TGEV infection. Identifying candidates that protect against TGEV may also be protective more broadly against other enteric coronaviruses and could be used as probiotics to protect pigs from disease.Overall, this proposal will give important insights into the impact of the gut microbiome on viral diseases of pigs and into microbiome-immune system interactions. This will not only give crucial information on understanding the microbiome's role in pigs' responses to disease but also allow to devise new strategies in combating viral, bacterial, and complex disease, particularly whilst reducing antimicrobial use.

冠状病毒在猪中出现相对频繁，最常见的是在幼猪中引起严重的肠道疾病。导致仔猪腹泻的肠道疾病影响它们的福利，并且是农民损失的主要来源，因为死亡率高，并且那些存活的猪在疾病和恢复期间通常生长减少。农民通常用抗生素治疗小猪，以保护它们免受可能导致腹泻的细菌的侵害，但这并不能保护它们免受肠道疾病的非细菌来源，如病毒，或由抗生素耐药细菌引起的疾病。有证据表明，栖息在动物肠道中的肠道微生物（肠道微生物组）在启动免疫系统以更快、更有效地应对病原体方面发挥作用。年轻的猪缺乏成熟的肠道微生物组，用抗生素治疗它们会进一步消耗它们的微生物组。鉴于微生物组在引发免疫系统对病原体做出反应方面的作用，在暴露于病原体之前引入能够引发免疫系统的微生物可能会导致对这些病原体的更强大的免疫反应，并导致更温和的疾病，或者没有疾病，我将操纵猪的微生物组，以改变肠道中存在的物种多样性，然后用传染性胃肠炎病毒（TGEV）。在整个试验期间，对猪进行插管，以允许进入其回肠微生物组。我将使用尖端技术来了解引入的微生物如何改变肠道微生物组和猪的免疫反应，我将确定微生物组中可能有助于免疫反应变化的功能潜力。我将在细胞和猪类器官中测试候选细菌，以确定触发稳态免疫信号变化并影响对TGEV感染反应的细菌。鉴定出能够预防TGEV的候选物也可能更广泛地预防其他肠道冠状病毒，并可用作益生菌来保护猪免受疾病的侵害。总体而言，该提案将为肠道微生物组对猪病毒性疾病的影响以及微生物组-免疫系统相互作用提供重要见解。这不仅将为了解微生物组在猪对疾病的反应中的作用提供关键信息，而且还可以设计新的策略来对抗病毒，细菌和复杂疾病，特别是在减少抗菌剂使用的同时。