Staphylococcus aureus induced immunosuppressive memory: consequences for bug and for host

Antimicrobial resistance by Staphylococcus aureus is a global epidemic. New approaches based on induction of immune responses that control/prevent S. aureus infection, are required. This necessitates a thorough understanding of the unique relationship cultivated by S. aureus with the immune system. In contrast to its invasive opportunism S. aureus is an important component of the normal human microflora. Amazingly, host-pathogen interactions in this context have never been comprehensively explored. This proposal will interrogate S. aureus symbiotic interactions with the immune system at the cellular and molecular level. I propose S. aureus exerts immunosuppressive pressures on the host during colonisation to facilitate persistence. This imprints a state of innate immunosuppressive memory that impedes expansion of antigen-specific T-cells, consequently impeding vaccine efficacy. To facilitate these investigations, I present a revolutionary approach involving development of a novel murine model of long-term nasal colonisation to enable mechanistic studies, in conjunction with studies that will profile immune responses in colonised humans, something, which thus far has never been undertaken. This proposal will establish if S. aureus can induce immunosuppressive innate immune training, which would represent a paradigm shift in the field which, to date, exclusively considers innate immune training to involve enhancement of pro-inflammatory responses.