Laboratory Research
Effective wound healing requires the carefully orchestrated activation of multiple host repair processes. Staphylococcus aureus, a prominent human pathogen, produces a range of bacterial antigens that have been implicated in impeding healing. Exacerbated tissue damage is thought to be driven by impairing the host ability to mount an effective immune response. However, the specific mechanisms remain poorly understood. We hypothesized that specific staphylococcal antigen’s would lead to prolonged immune cell activation, and directly impede human wound healing.
Methods:
Here we explored the effect of the well characterized staphylococcal antigen TSST-1 on immune cell recruitment/activation, and healing kinetics in ex vivo human wounds. In tandem we employed murine in vivo studies to determine the molecular pathways that underlie compromised tissue repair in the presence of TSST-1. Innate and adaptive immune cells, extracted from healthy and chronic wound tissue, were analyzed using multi-colour flow cytometry. Ex vivo wound healing was assessed via confocal microscopy.
Results: We show that TSST-1 stimulated ex vivo wounds in healthy donor skin adopted an immunological profile that closely resembled freshly collected chronic wound tissue from diabetic patients. Specifically, a higher proportion of activated effector immune cells (especially T cells) were detected in TSST-1 exposed wounds. RNA-seq and histological analysis of TSST-1-treated excisional wounds in Balb/c mice was used to assess the downstream molecular and cellular pathways. We show that TSST-1 significantly delays healing by upregulating activated adaptive immunity while impeding cellular migration, proliferation and extracellular matrix remodeling.
Discussion:
These studies provide new insight into the diverse effects of the staphylococcal antigen TSST-1 on immunological and molecular aspects of wound repair. Improved understanding of host-microbe interactions is essential for the future development of targeted therapeutic strategies to overcome the detrimental effects of Staphylococcus-associated wound infections on healing.