Shining a light on molecular mechanisms that potentiate phagocytosis of bacteria

forthcoming

Antibiotics are among the greatest medical achievements of the 20th century and have significantly extended human lifespan. Nevertheless, bacterial infectious diseases continue to be a leading cause of death worldwide. Antibiotic treatment failures are common and typically linked to antimicrobial resistance (AMR), though resistance genes are not always present in such cases. Innate immune cells, particularly phagocytes serve as the first line of defence against infection, but they can paradoxically become reservoirs for certain pathogens. Within host cells, these bacteria are shielded from many antibiotic classes and may adopt persister phenotypes that confer tolerance, enabling them to survive phagocytosis and reinfect patients. My conviction is that tackling AMR and tolerance requires sophisticated approaches, where we need to find complementary pathways between immune response and antibiotic activity. Recent advances in super-resolution imaging will allow me to scrutinise molecular mechanisms in both host and pathogen that directly influence the outcome of phagocytosis. I propose to i), develop a super-resolution model of phagocytosis, using major AMR pathogen Staphylococcus aureus and host Drosophila melanogaster, to provide ground-breaking insights into the mechanisms of infection; ii), investigate how bacteria coordinate the cell cycle during infection, to identify vulnerabilities and test strategies to kill the internalised pathogens and iii), explore the roles of the host centrosome during phagocytosis, to determine how this organelle regulates the cytoskeleton and assess its potential as a target for immunomodulation. I will harness cutting-edge imaging technology to significantly advance the field of host-pathogen interactions. My main objective is to identify molecular targets and pathways that potentiate phagocytosis of bacteria and use that knowledge to develop synergistic therapies, which I hope can help reduce the global burden of AMR.