Staphylococcus aureus bacteria hide inside human immune cells called macrophages, surviving where they should be killed. This project will identify exactly which macrophage responses are needed to clear these hidden bacteria. The problem is that *S. aureus* causes persistent infections—from skin abscesses to life-threatening sepsis—that resist standard antibiotics. Clinical and animal evidence shows that bacteria surviving inside macrophages drive much of this disease. Current treatments cannot reach this intracellular reservoir. Host-directed therapies, which boost the macrophage's own killing mechanisms, could work where antibiotics fail, but researchers do not know which specific macrophage responses to target. The researcher will use six pairs of staphylococci that survive differently inside human macrophages. By comparing the host's gene activity and metabolism across these pairs, and integrating the data with existing knowledge, they will produce a shortlist of priority genes for future drug development. This is fundamental science. It does not produce a therapy immediately. But similar work on host-pathogen interactions has previously revealed targets for treatments against tuberculosis and *Salmonella*. A clearer map of the macrophage's anti-staphylococcal toolkit could eventually lead to drugs that cure chronic *S. aureus* infections without relying on new antibiotics.
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Staphylococcus aureus can survive and persist within macrophages. Clinical evidence and animal studies indicate that this intracellular pool of bacteria is significant in disease pathogenesis. Host-directed therapies to re-engage macrophage microbicidal mechanisms to eradicate these intracellular bacteria could therefore improve clinical outcomes. However, despite extensive research, the specific macrophage responses required to achieve this remain incompletely defined. In this project I will build on my previous novel approach of using the pathogen as a tool to identify the critical responses involved. In brief, I will employ six pairs of staphylococci that exhibit differential survival in human monocyte-derived macrophages (hMDM). Through a meta-analysis of bacterial genes involved in disease pathogenesis and intracellular survival (using the meta-analysis by information content [MAIC] algorithm), I have already prioritised gene targets to test their importance during intracellular survival in hMDM, using mutants from the Nebraska Transposon Mutant Library. In addition, I will compare the intra-macrophagic survival of S. aureus vs. S. epidermidis, and will also examine a macrophage-passaged S. aureus strain with enhanced intra-macrophagic survival. The bacterial strain pairs will be used to challenge hMDM in a paired design to profile the transcriptional and metabolic responses associated with strain-dependent differences in intra-macrophagic survival and clearance. I will then use MAIC to integrate these datasets with each other, and with published data regarding the host response to S. aureus. Overall, this project aims to generate an integrated, data-driven shortlist of genes for future investigation as targets for host-directed therapies for S. aureus disease.
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