Friday, May 9, 2025
5/9/2025
Modulation of neutrophil-endothelial interactions by ADAM10 - PROJECT SUMMARY Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity, mortality, and economic loss. The unique ability of S. aureus to cause a wide range of infections and toxin- mediated syndromes highlights this organism’s vast array of encoded virulence factors, and ability to utilize these factors to modulate the host-pathogen interaction. While each of the body's tissues that can be infected by S. aureus pose distinct physiological and immunological challenges to the microbe, we are interested in understanding whether S. aureus leverages a common mechanism that is ‘tissue-independent’ to subvert host immune defense. Extensive research, including our own studies, supports the targeting of S. aureus -toxin (Hla) as a virulence factor to protect against infection. The interaction of Hla with its eukaryotic receptor ADAM10 provides an additional window of opportunity to evaluate whether host-specific factors that modify ADAM10 expression or cellular activity impact susceptibility to S. aureus disease. We have previously demonstrated that S. aureus incites endothelial injury through VE-cadherin cleavage and elicits platelet-neutrophil clustering on the injured endothelium dependent on Hla-ADAM10 interaction. As neutrophil-endothelial cell interactions are well described to play a critical role in host defense to infection, we now propose to understand on a mechanistic basis how ADAM10 modulates key endothelial-neutrophil interactions early in the context of S. aureus infection. Relying on a unique repository of transgenic mice, in vivo imaging capabilities, and microbiologic tools to evaluate S. aureus within the tissues, we will generate a spatiotemporal analysis of the interaction between neutrophils and the endothelium. These studies will focus on the initial cellular and molecular interactions that shape the early outcome of infection in distinct tissues, assessing the role of ADAM10 as a ubiquitously expressed protease that contributes to pathogenesis. Through this research program, we will have an opportunity to define a how the host-pathogen interaction may be shaped by a central defect in the early host response. The successful completion of these studies may enable analysis of short-term targeted therapy of ADAM10 to improve disease outcome.
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