Trespassing the defensive lines cardiovascular infection

Sepsis is one of the major causes of mortality in critically ill patients worldwide. The bloodstream is a normally sterile environment but upon infection a dysregulated and deleterious inflammatory response can be induced. The damage from the inflammatory response leads to organ failure and ultimately death. Routinely sepsis is associated with the bacteria Staphylococcus aureus. While the pathophysiology of severe sepsis is not well defined it is accepted that sepsis-associated mortality is related to the host response which involves a multitude of cell types, inflammatory mediators and coagulation factors. The endothelium is a major target of sepsis-induced events as it is among the first cells in the body to come into contact with circulating bacteria. This aim of this thesis was to investigate the role partaken by endothelium in mediating the sepsis phenotype and focus on the potential value of the endothelium as a target for sepsis therapy.

Previous studies have identified several mechanisms that S. aureus uses to bind to endothelial cells using a range of different models. Cognisant of ensuring that we are using as close to a physiological model of infection as possible, we developed a model using conditions that closely mimic conditions experienced in the vasculature. Using this model we identified a previously undescribed interaction between S. aureus and human endothelial cells. We identified that S. aureus clumping factor A binds plasma fibrinogen and crosslinks to Human Endothelial cell integrin αVβ3. This interaction results in the generation of an intracellular signal that leads to apoptosis, loss of cell numbers and increased vascular permeability, all clinical signs of the sepsis phenotype in humans. Using a strain deficient in expression of clumping factor A or blocking the endothelial cell integrin αVβ3 using a c(RGDfV) peptide significantly reduced the binding interaction and the associated dysfunctional effects apoptosis, loss of cell recovery and increased vascular permeability. Our results suggest that using the c(RGDfV) (currently developed as EMD121974) may be useful in the early treatment of sepsis.