Tuning Immunity:Regulation and Functions of CaMKII at the Host-Pathogen Interface

Bacterial diarrhoeal diseases represent a significant global health burden, particularly in vulnerable populations such as young children. A large proportion of these cases can be attributed to Salmonella and Shigella species, which have been flagged by the WHO and CDC as bacterial families posing a serious public health threat due to the rise of multi-drug resistant strains. A deep understanding of how these pathogens cause disease and how our immune system responds to infections is essential for the development of novel therapies. Precise regulation of immune signalling and the integration of multiple signal transduction cascades are critical in the rapid establishment of an effective immune response. While canonical pathways linking microbial detection to transcriptional responses are well characterised, the molecular signals fine-tuning inflammatory signalling remain poorly understood. Our published and preliminary findings support the calcium-regulated kinase CaMKII as a modulator of inflammatory sensing, boosting immunity against enteric invasive bacteria. Thus, the CaMKII axis stands as an evolutionary conserved target for diverse pathogens seeking to evade host immunity. This proposal will (1) Determine the dynamics of CaMKII activation during infection and how it integrates with inflammatory signalling; (2) Define the immune regulatory functions of CaMKII signalling using animal models of infection; and (3) Identify and characterise pathogenic factors that antagonise CaMKII to evade immune detection. This research plan at the interface between host and pathogen will reveal new mechanisms of immune sensing and pathogenesis. This will identify biological targets for novel antimicrobial and host-directed therapies