Hijacking of the 'Don't Eat Me' signal by Group B Streptococcus

Group B Streptococcus (GBS), or Streptococcus agalactiae, is the leading cause of sepsis and meningitis in human neonates and an emerging cause of invasive disease in adults. The detection of antibody-opsonised bacteria by phagocytic cells, like macrophages, elicits the ‘Eat Me’ signal that provides a critical arm of the host immune defence. Notably, bacterial pathogens often have immune evasion strategies to escape these processes. However, not all immune evasion mechanisms are understood for GBS and bacterial pathogens. Since bacterial pathogens often target specific cellular receptors, the host lab has performed a novel high-throughput screening of 1500 human cellular receptors for their interaction with GBS to uncover new host-pathogen interactions. This analysis revealed that the top hit is an inhibitory receptor called SIRPα expressed on macrophages. SIRPα detects CD47 on healthy cells to prevent macrophages from phagocytosing them. This is known as the ‘Don't Eat Me’ mechanism. Here, I hypothesise that bacterial pathogens like GBS interact with SIRPα to hijack the ‘Don’t Eat Me’ signal and evade macrophage phagocytosis and killing. I will use GBS as a study system. My objectives are to 1) use biochemical and structural approaches to define the GBS interaction with SIRPα, and use sophisticated genetic mutagenesis approaches to generate isogenic GBS strains that do not interact with SIRPα, 2) use cell and tissue infection models to determine the functional consequences of GBS targeting SIRPα. Overall, I will uncover a novel immune evasion strategy of GBS and establish whether pathogenic bacteria hijack SIRPα for immune evasion. More broadly, I will establish for the first time that our new high-throughput screening approach can uncover novel bacteria-human receptor interactions that have functional consequences in bacterial infection biology.