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

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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.