Role of STAT3 in bovine protozoan infection (360G-Wellcome-211894_Z_18_Z)

Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic transcription factor and signalling molecule. Whole animal knock-out mice are embryonic lethal, while cell-specific KO present with differing phenotypes including exacerbated and reduced inflammatory responses dependent on the cell type altered. Using a bovine model of protozoan challenge, we have noted an age-related difference in monocyte responses. Differential gene expression analysis indicates that the STAT3 network is more robustly activated in neonates and this corresponds with enhanced parasite clearance[CJ1] . We now propose to test the actions of STAT3 in two systems to determine if age-dependent resistance to infection is dependent on STAT3. Firstly, bovine neonatal and adult monocytes will be challenged with the abortifacient Neospora caninum; the cytokine response and parasitemia will be measured against a background of STAT3 chemical inhibition. Secondly, using a novel bovine intestinal organoid model, the role of STAT3 in N. caninum infection of the small intestinal epithelium will be tested. Differentiated organoids will be challenged under conditions in which STAT3 has been acutely inhibited, and the cytokine response and parasitemia measured. This work will determine if the differential age-related response to infection extends beyond the monocyte and is STAT3 driven.