Research projects

Closely related bacterial strains can differ dramatically in their ability to cause disease. A major factor behind this variation lies in adhesins—surface proteins that mediate binding to host tissues and initiate infection. This work package investigates how adhesin diversity influences bacterial virulence and aims to identify molecular features that distinguish high- and low-virulence strains.

We will establish the StraDiVarious Variant Collection (StraVaC), a curated resource linking ESKAPE pathogen genomes to phenotypic and clinical data on infection severity. Using comparative genomics, we will analyse the evolution and diversity of adhesomes, the complete set of adhesins expressed by a bacterial strain, within and across species. A key method will be protein feature architecture-aware phylogenetic profiling, allowing us to detect structural and evolutionary changes in adhesins associated with virulence. By integrating adhesome profiles with virulence data, we will use machine learning to identify features predictive of pathogenicity. Selected strains - natural variants and mutants of A. baumannii, P. aeruginosa, and S. aureus - will be analysed for biofilm formation and host cell adhesion. Quantitative proteomics will reveal strain-specific differences in adhesin expression and identify host receptors involved in adhesion, invasion, and immune evasion. To study the functional relevance of key variants, we will collaborate with experimental partners from the consortium using organ-on-chip systems and 3D human tissue models that replicate host environments and responses. Together, these approaches will provide an integrated understanding of how adhesin variation shapes bacterial virulence and support the development of genome-based tools for infection prediction and control.

We aim to understand binding of pathogen variants to host cells, how variants manipulate host cell responses, and to develop innovative organ-on-chip models to study strain and variant adhesion/colonisation of the host. We will use a combination of in vitro assays, cell lines, human cells and tissues, and organ-on-a-chip models, to understand how pathogenic variants interact with host cells (adhesion, colonization) and manipulate their responses (cell signaling, inflammation).

There is an urgent need to develop laboratory models of humanised organs to reduce dependence on animal models in scientific research. Animal models are expensive, time-consuming, ethically problematic, and often poor predictors of human biological responses. To address this, we aim to create next-generation humanised models of the gut and vasculature using advanced organ-on-chip technology to study bacteria-host interactions. This technology enables more accurate modelling of human tissues and organ-level structures compared to traditional cell culture methods. By using organ-on-chip (OoC) systems, we can observe and control these interactions with unprecedented precision, offering new insights into the mechanisms of colonisation and infection that were previously unattainable. Gut-on-chip models will be developed at Institut Pasteur, using patients derived intestinal organoids maturated in OoC (Institut Pasteur, France) to analyse the dynamics of bacterial adhesion, colonisation and invasion. Human vasculature-on-chip models will be developed at Heriot-Watt University, Edinburgh and used to investigate mechanisms of bacterial blood infection and colonisation alongside collaborators at Lund University.

We will perform structural characterization of adhesin-host receptor interactions at an atomic scale, and use this information to understand differences between high-virulent and low-virulent bacteria. This will also allow for identification of potential drug targets.

Development of new diagnostic, anti-adhesion and antimicrobial strategies requires a comprehensive understanding of adhesin-host receptor binding and associated signalling events. To achieve this, we focus on the interaction networks of key bacteria-host protein complexes, and on the effect of small variations in virulence factor sequence on structure and function. We will study the dependence of adhesin sequence length and repeat number on the conformational dynamics (bending, twisting) of the molecule. This will be achieved by combining high-resolution structural biology methods such as cryo-EM and structural EPR with different modelling approaches. Similarly, we will study the interactions and interaction networks of key adhesins from ESKAPE pathogens using a combination of NMR, cryoEM and integrative modelling. CyroET of adhesins in different conditions and with different host cell models will be used to test adhesion capacity of pili and develop anti-adhesion strategies.

We will develop rapid, innovative biosensors for diagnostics and advanced bioassay systems to study how host cells bind and respond. We will then use these tests to explore links with antimicrobial susceptibility testing (AST).

Our bioassays and diagnostic devices will be based on the targets and interactions identified and characterised for ESKAPE pathogens. The aim is to quantify interactions and develop rapid tests and test kits to detect, screen, and measure virulence traits. Sensor binding assays will be developed based on novel methodologies such as recently developed nanoparticle labels and, emerging materials and approaches for electrochemical biosensing and stable recognition elements such as aptamers and affimers. Diagnostics flow cartridges and spheroid-on-a-chip devices will be designed and tested and the optical and electrochemical sensing approaches will be integrated to obtain dynamic systems to quantify binding. The ultimate aim is to generate diagnostic devices for commercialisation.