Unraveling tissue microenvironment dynamics in the pathogenesis of Group A Streptococcal necrotizing soft tissue infections

Necrotizing soft tissue infections (NSTI) are life-threatening infections mainly caused by Group A Streptococcus (GAS). GAS NSTI tend to affect younger, healthy individuals, often presenting no bacterial portal of entry.

These infections are often due to transient bacteremia, where GAS disseminate from common niches (e.g. throat), to otherwise sterile tissues.

Compared to other etiologies, GAS NSTI preferentially affect the extremities, but factors contributing to such tissue tropism are unknown. This research investigates the complex local host-pathogen interactions in the tissue microenvironment.

We will identify tissue-specific signatures (e.g. cell types and immune responses) driving GAS NSTI at varying anatomical sites through integration of clinical data with multiomics data from tissue and plasma samples.

Spatial context to the identified signatures will be obtained by high-dimensional immunofluorescence microscopy of patient biopsies. The results will guide the development of tailored in vitro 3D immunocompetent tissue models for mechanistic studies.

Lastly, the connection between the relevant signatures and the metabolic adaptations of GAS and host cells will be explored through proteomics.

Ultimately, this project will provide novel insight into the role of the microenvironment in NSTI and the factors leading to it tissue tropism.

The outcomes from this research project will identify novel targets for precise diagnostics and personalized therapeutic strategies.