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

冠状病毒在猪中出现的频率相对较高，最常见的是在仔猪中引起严重的肠道疾病。引起仔猪腹泻的肠道疾病影响仔猪的健康，是农民损失的主要来源，因为死亡率很高，而那些存活下来的仔猪在患病和恢复期间往往生长缓慢。农民通常用抗生素治疗仔猪，以保护它们免受可引起腹泻的细菌的侵害，然而，这并不能保护它们免受非细菌来源的肠道疾病，如病毒，或由抗生素耐药细菌引起的疾病。有证据表明，栖息在动物肠道内的共生微生物，即肠道微生物群，在启动免疫系统以更快、更有效地应对病原体方面发挥着作用。仔猪缺乏成熟的肠道微生物群，用抗生素治疗会进一步消耗它们的微生物群。鉴于微生物组在启动免疫系统对病原体作出反应方面的作用，在暴露于病原体之前引入能够启动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，并导致较轻的疾病，或者没有疾病，正如在成年猪中所看到的那样。在感染传染性胃肠炎病毒（TGEV）之前，我将对猪的微生物组进行操作，以改变肠道中存在的物种多样性。这些猪将被插管，以便在整个试验期间进入回肠微生物群。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群和猪的免疫反应，我将确定微生物群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。确定对TGEV具有保护作用的候选病毒也可能对其他肠道冠状病毒具有更广泛的保护作用，并且可以用作保护猪免受疾病侵害的益生菌。总的来说，这一建议将为肠道微生物组对猪病毒性疾病的影响以及微生物组与免疫系统的相互作用提供重要的见解。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重要信息，而且还允许设计对抗病毒，细菌和复杂疾病的新策略，特别是在减少抗菌素使用的同时。

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.