Understanding how interaction with the host influences virulence and antimicrobial resistance in Staphylococcus aureus

Secondary Supervisor(s): Dr Tim Overton

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Microbiology)

Project Outline

Staphylococcus aureus is a leading pathogen globally and also asymptomatically colonises the upper respiratory tract of more than 30% of humans. The staphylococcal pathogenesis lab focuses on understanding the factors that contribute to the success of Staphylococcus aureus as a commensal and pathogen and using this information to discover new targets for decolonisation or treatment of infection. Bacterial adhesion is a crucial step during infection. Staphylococcus aureus possesses a vast repertoire of adhesins that facilitate attachment to host molecules and surfaces. The aim of this project is to advance our understanding of the bacterium-host interaction by discovering how S. aureus responds to attaching to a host surface, and to identify how this changes susceptibility to antibiotics or host defences.

Key Objectives

1. Establish how expression and activity of S. aureus adhesin proteins is modulated by the sensing of host proteins and surfaces.

2. Discover how S. aureus virulence factor production is modulated by interaction with host proteins and surfaces.

3. Discover how susceptibility to antimicrobial agents and host defences changes following interactions with host molecules.

The student will join a collegiate interdisciplinary research group within the Institute of Microbiology and Infection (IMI) at University of Birmingham and benefit from collaboration between Professor Joan Geoghegan and Dr Tim Overtons’ groups. The student will be trained in a range of molecular microbiology and infection biology techniques, single cell analysis, transcriptional profiling and proteomics.

References

Da Costa TM et al., (2022). Fibronectin binding protein B binds to loricrin and promotes corneocyte adhesion by Staphylococcus aureus. Nature Communications. 13: 2517.

Geoghegan JA & Dufrêne YF (2018). Mechanomicrobiology: How Mechanical Forces Activate Staphylococcus aureus Adhesion. Trends Microbiol. (8):645-648.

Geoghegan JA & Foster TJ (2017) Cell Wall-Anchored Surface Proteins of Staphylococcus aureus: Many Proteins, Multiple Functions. Curr Top Microbiol Immunol. 409:95-120.

Understanding interactions between Staphylococcus aureus, Streptococcus pneumonia and Corynebacterium within the human nasal microbiota

Secondary Supervisor(s): Dr David Cleary

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Microbiology)

Project Outline

Staphylococcus aureus and Streptococcus pneumoniae are leading human pathogens and also asymptomatically colonise the upper respiratory tract of more than 30% of humans. Corynebacterium species are abundant in the human nasal cavity. Several studies to date have identified antagonistic or synergistic relationships between bacteria but this has usually involved culture of bacteria under laboratory conditions or the use of animal models that do not reliably capitulate the environment of the human nasal cavity. This project aims to use innovative co-colonisation models to build a synthetic microbial community where all three species, or combinations thereof are cultured in an in vitro tissue model of the human nasal epithelium cultured at the air liquid interface to identify competitive interactions, or synergistic interactions that exist between the co-colonising species. This approach addresses the limitations of traditional laboratory cultures and animal models and will enhance our understanding of microbial interactions in the nasal cavity, potentially informing future treatments for infections caused Staphylococcus aureus and Streptococcus pneumoniae.

References

Brugger SD, Bomar L, Lemon KP (2016) Commensal–Pathogen Interactions along the Human Nasal Passages. PLoS Pathog 12(7): e1005633. https://doi.org/10.1371/journal.ppat.1005633.

Ortiz Moyano, R. et al., Antagonistic Effects of Corynebacterium pseudodiphtheriticum 090104 on Respiratory Pathogens. Microorganisms 2024, 12, 1295. https://doi.org/10.3390/microorganisms12071295.

Uncovering bacterial drivers of Staphylococcus aureus bloodstream infection

Secondary Supervisor(s): Dr James Scriven

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Immunology, Microbiology)

Project Outline

Staphylococcus aureus bacteraemia (SAB) is among the most common and serious bacterial infection affecting 13,000 people in England alone each year. Mortality is between 10-30% and the average length of stay in hospital in the UK is 22 days, with 23% being readmitted within a 12-week period.

Treatment of SAB can be difficult. Whilst some patients experience a “simple” bacteraemia, others develop “complicated” infections with multiple additional foci of infection including soft tissue, bone and joint, cardiac, endovascular and prosthetic material infections. Current management of SAB is therefore not optimal, even when the bacteria are susceptible to an antibiotic in vitro. This project will explore the development of SAB and how this is influenced by the molecular characteristics of the bacteria. To achieve this, a novel CRISPR interference library will be generated in a bloodstream isolate of S. aureus to evaluate the contribution of the entire bacterial genome to the establishment of SAB using an ex vivo human whole blood survival model. Potential contributors identified from the screen will be validated through further analysis, including gene knockouts and gene expression studies. The outcome of this project will be a fundamental understanding of the bacterial factors contributing to the development of SAB, an optimised ex vivo model for studying SAB, and a set of new validated targets for the treatment of S. aureus infection.