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

Porcine enteric disease are major concerns of animal health and welfare as well as economic burdens on the pork industry. There is growing evidence that the composition of the gut microbiome has an impact on the immune response to pathogens. However, in pigs the effect of viral infection on the gut microbiome, and in turn, the effect of the gut microbiome on disease morbidity is poorly understood and understudied. It is well understood that young pigs have substantially higher morbidity and mortality from enteric disease than adults, that young pigs have underdeveloped microbiomes, and that the microbiome has a role in immune development. Recent work has demonstrated that the microbiome impacts immune function in the gut through stimulation of low level interferon-beta expression which primes the immune system to respond to pathogens, and that microbes can affect response to viruses in vitro. In this project I will manipulate the gut microbiome of cannulated pigs using antibiotics, faecal microbiome transplants and probiotics prior to infection with transmissible gastroenteritis coronavirus (TGEV). I will use long-read sequencing to assemble and characterise the gut microbiome of pigs before, during and after infection. These data will be used to determine how the gut microbiome changes over the course of infection, whether microbiome manipulations persist during infection, and to identify bacteria that may play a functional role in altering morbidity. Additionally I will determine which groups have the lowest morbidity during infection with TGEV, and if increased diversity is associated with lower morbidity in pigs. I will also detect changes in immune signalling between different groups over the course of infection. Bacteria that were enriched pre-infection only in pigs with the lowest morbidity will be tested in vitro in cell lines and enteroids to determine if these bacteria have an impact on immune signalling and improve immune response to TGEV infection.