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The role of copper resistance in Staphylococcus aureus infection

Primary Supervisor: Professor Julie Morrissey, Department of Genetics and Genome Biology

Secondary supervisor: Dr Joan Geoghegan, University of Birmingham, Professor Julian Ketley, Professor Peter Andrew, University of Leicester, Dr Kevin Waldron (University of Newcastle)

PhD project title: The role of copper resistance in Staphylococcus aureus infection

University of Registration: University of Leicester

Project outline:

Excess copper is highly toxic and forms part of the host innate immune system’s antibacterial arsenal, accumulating at sites of infection and acting within macrophages to kill engulfed pathogens.

All bacteria possess mechanisms to resist the toxicity of the essential micronutrient copper. However, our recent publications show that methicillin resistant Staphylococcus aureus (MRSA) have acquired additional copper hyper-resistance mechanisms (Purves et al., 2018, Zapotoczna, 2018) that increase survival during their interaction with human immune cells.

The highly virulent community acquired MRSA USA300 has acquired a novel copper resistance locus that is uniquely associated with the methicillin resistance element (Purves et al., 2018). This locus confers copper hyper-resistance and is required for S. aureus USA300 intracellular survival within macrophages. These genes are additional to existing core genome copper resistance mechanisms, and are not found in typical S. aureus lineages, but are increasingly identified in other emerging pathogenic isolates and other pathogenic bacteria.

Our current transcriptional data show that the presence of excess copper alters the expression of several metabolic pathways and virulence genes.

The aim of this project is to investigate the role of copper resistance mechanisms in the increased infectivity of CA-MRSA.

Objectives are to:

  1. Establish the molecular mechanisms involved in the copper-responsive regulation of virulence factors.
  2. Determine the importance of copper-regulated metabolic pathways in

(a) resistance to copper toxicity.

(b) survival against human innate immunity.

The student will be part of a lively and friendly interdisciplinary research group and will be trained in a wide range of molecular microbiology techniques including transcriptional analysis, proteomics, tissue culture, fluorescence and electron microscopy to investigate the impact of additional copper resistance mechanisms on host-pathogen interactions.

References:

  1. Purves J, Thomas J, Riboldi GP, Zapotoczna M, Tarrant E, Andrew PW, Londoño A, Planet PJ, Geoghegan JA, Waldron KJ, Morrissey JA. A horizontally gene transferred copper resistance locus confers hyper-resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages. (2018) Environ Microbiol. doi: 10.1111/1462-2920.14088.
  2. Zapotoczna M., Pelicioli-Riboldi G., Moustafa AM, Dickson E., Narechania A., Morrissey J A., Planet PJ., Holden MTG., Waldron KJ., Geoghegan JA. Mobile genetic element-encoded hypertolerance to copper protects Staphylococcus aureus from killing by host phagocytes (2018) MBio. 2018 9(5). pii: e00550-18.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology

    Techniques that will be undertaken during the project:

    • Microbiological techniques

    • RNA and DNA analysis

    • Bioinformatics

    • Metalloproteomics

    • Tissue culture

    • Imaging

    • Metal analysis

    Contact: Professor Julie Morrissey, University of Leicester