Molecular dissection of Staphylococcus aureus in Atopic Dermatitis Using a Human Skin Organoid model

About the Project

Title: Molecular dissection of Staphylococcus aureus in Atopic Dermatitis Using a Human Skin Organoid model

Synopsis: This project investigates how skin-tropic Staphylococcus aureus lineages interact with atopic dermatitis skin using human skin organoid models. Comparative infections and dual RNA-seq will define strain-specific, host–pathogen transcriptional responses, and molecular mechanisms driving inflammation and barrier disruption, guiding new antimicrobial strategies.

Details: Atopic dermatitis (AD) is an inflammatory skin disorder that follows a relapsing and remitting course, characterized by epidermal barrier dysfunction, immune dysregulation, and disruption of the skin microbiome. Most AD patients are persistently colonized by Staphylococcus aureus, and its presence strongly correlates with disease severity, recurrent flares and treatment resistance. While some S. aureus lineages exhibit a tropism for skin, the molecular basis for their preferential colonization and virulence in the cutaneous niche remains poorly understood. There is inter-individual variation in AD patients’ propensity for S aureus infection, but this is also poorly understood. Current treatments include anti-septic and antibiotic therapies, but these have side-effects and can promote development of antimicrobial resistance.

This cross-disciplinary project aims to elucidate the mechanisms underpinning S. aureus–host interactions in AD by combining comparative infection assays with dual-transcriptomic profiling (bacterial and human) in an ex vivo human skin organoid model. The organoid is created using human primary skin cells, to form an artificial epidermis in which the structure, ultrastructure and molecular components mirror human skin in vivo (Elias et al, 2019). The model can be manipulated by selected gene knockdown to represent genetic risk for AD (Elias et al, 2019b).

In the first phase, the project will compare S. aureus strains representing major skin-associated clonal complexes (e.g., CC8 [USA300], CC1, CC30, and CC121) engineered to produce GFP, in order to examine colonization efficiency, barrier disruption, and virulence within the skin organoid system. Quantitative imaging, bacterial load assays, and cytokine profiling will identify lineage-specific phenotypes linked to skin adaptation and pathogenicity. Secondly, a representative skin-tropic strain will be selected for dual RNA-seq analysis during infection of AD-modelled organoids to identify the transcriptional responses of both host and bacterium during infection.

These data will reveal how S. aureus adjusts its metabolic and pathogenic pathways in response to the AD microenvironment, and how keratinocytes, fibroblasts as cells at the direct interface with skin microbiome respond to infection through innate and acquired immune signalling (Brown, 2024). Finally, based on the transcriptomic analysis, targeted experiments using isogenic S. aureus mutants of selected determinants will validate the roles of specific bacterial factors in driving inflammation, barrier breakdown, or immune evasion.

In summary, by integrating comparative microbiology, organoid modelling, and dual transcriptomics, this project will generate a comprehensive picture of how skin-tropic S. aureus lineages exploit the compromised AD barrier. The mechanistic data resulting will provide a foundation for new antimicrobial or barrier-restorative therapies and will advance human skin organoids as a powerful platform for infection biology.

Potential impact: Mechanistic insights into S. aureus–host interactions in atopic dermatitis could enable development of barrier-restorative treatments, targeted anti-virulence therapies, or microbiome-modulating strategies. Identified bacterial determinants and host pathways may inform precision therapeutics and guide screening of novel antimicrobials or biologics using human skin organoid models.

Training: The student will join a highly successful research environment spanning three leading laboratories with complementary research interests. The collaborative supervision will provide excellent training opportunities across the spectrum of molecular microbiology to human cell biology and molecular genetics, with a strong translational relevance guided by clinical expertise. This is a cross-disciplinary project offering a unique training experience for the successful student, offering many possible career routes post-PhD. In addition, the student will have access to a wide array of training courses in the University of Edinburgh’s Institute for Academic Development that provide additional skills and expertise that are valuable whatever the career destination of the student.

Apply: All applications must be submitted through the Future Medicine PhD fellowships website.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.

The fellowships are open to students who are eligible for home fees at Edinburgh - i.e. you must be a UK national, or have settled status, and have. been "ordinarily resident" in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.