Position title: Pathobiological Sciences
Cell Adhesion & Cytoskeleton; Molecular & Genome Biology of Microbes
The vascular endothelium is recognized as the target of pathological inflammation as well as the cause of vascular pathologies. Infective endocarditis is, by definition, an infection of the heart endothelium. Endothelial cell responses critically contribute to early innate immune system activation. This is central to both immune protective and pathological responses that play a role in the pathogenesis of various cardiovascular diseases, such as atherosclerosis. In pathological responses, the endothelium becomes dysfunctional through multiple mechanisms including reduced nitric oxide bioavailability, increased activation, impaired barrier function, or impaired vascular remodeling/angiogenesis. The physiologic impact of enterotoxins on the vascular endothelium and on S. aureus endocarditis causation is largely unknown. Hence, we are currently addressing whether enterotoxins target the endothelium and impair critical cellular functions as a mechanism to advance endocarditis development. We have evidence that Staph enterotoxins/superantigens directly impair wound healing and inhibit important angiogenic factors in human endothelial cells. In experimental endocarditis in rabbits, enterotoxin C deletion results in tiny vegetations that are completely endothelialized, suggesting that enterotoxins may target vascular remodeling to promote disease. We are currently investigating the underlying molecular mechanisms associated with wound healing/angiogenesis defects and the biological functions of enterotoxins directly driving those processes.