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Bacterial survival in the host and in the environment is promoted by horizontal gene transfer of additional metal resistance genes


Project Description

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 tolerate the inherent toxicity of the essential micronutrient copper. However, our recent publication (Purves et al., 2018) showed that the highly virulent, epidemic, community acquired methicillin resistant Staphylococcus aureus USA300, which shows altered infectivity compared to typical S. aureus, has acquired an additional copper hyper-resistance mechanism.

Our data show that this novel, horizontally gene transferred copper resistance locus is associated with the SCCmec elements of USA300. 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 emerging pathogenic isolates.

Our hypothesis is that acquisition of copper hyper-resistance via horizontal gene transfer plays a crucial role in the emergence of S. aureus strains, and potentially other pathogenic bacteria, with increased infectivity conferred through their improved resistance to the copper-dependent killing mechanisms of the host’s immune cells.
L. monocytogenes is a major food borne pathogen, commonly found in food processing environments, that causes life threatening listeriosis after eating contaminated foods including processed cheeses, meat and vegetables. Multiple genes for heavy metal resistance have been identified in L. monocytogenes.

The aim of this project is to investigate the role of related additional copper resistance mechanisms in increased infectivity and environmental persistence of Listeria monocytogenes.

Techniques that will be undertaken during the project

Microbiological techniques, RNA and DNA analysis, bioinformatics, biochemistry, metalloproteomics, transcriptomics, infection models.

Available to UK/EU applicants only
Application information
https://www2.le.ac.uk/research-degrees/doctoral-training-partnerships/bbsrc

Funding Notes

4 year funded BBSRC Midlands Innovative Biosciences Training Partnership Studentship (MIBTP)
The funding provides a stipend at RCUK rates and UK/EU tuition fees for 4 years

References

Baker et al., 2011, ‘The Staphylococcus aureus CsoR regulates both chromosomal and plasmid-encoded copper resistance mechanisms,’ Environ. Microbiol. 13:2495-2507.
Corbett D, Schuler S, Glenn S, Andrew PW, Cavet JS, Roberts IS. 2011 The combined actions of the copper-responsive repressor CsoR and copper-metallochaperone CopZ modulate CopA-mediated copper efflux in the intracellular pathogen Listeria monocytogenes. Mol Microbiol. Jul;81(2):457-72
Purves et al. 2018 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. Environ Microbiol. 20(4):1576-1589.
Zapotoczna et al. 2018. Mobile genetic element-encoded hypertolerance to copper protects Staphylococcus aureus from killing by host phagocytes. (2018) MBio. 9(5). pii: e00550-18.

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