Investigating the impact of neutrophil extracellular traps and peptidylarginine deiminase 4 in Gram-positive sepsis

Sepsis is a significant health care problem, with mortality rates remaining at 30% despite years of research and implementation of new intervention therapies. The pathologies of sepsis result not only from an infection, but also from the hyperinflammatory host response. Most research, particularly in animal models, is currently on polymicrobial sepsis or Gram-negative bacterial products, which does not necessarily match the clinical cases of Gram-positive sepsis, including Staphylococcus aureus. S. aureus is known to be causative in infectious pathologies, including skin abscesses, endocarditis, and sepsis. S. aureus is a potent inducer of neutrophil extracellular traps (NETs), or protein-containing DNA strands released from white blood cells. These NETs form during S. aureus systemic infections and likely promote an exacerbated immune response and vascular occlusion. With this project, we aim to understand the virulence factors on S. aureus which drive NET formation, the role of the blood protein VWF in promoting NET formation, and the mechanistic role for the enzyme peptidylarginine deiminase 4 (PAD4) in promoting disease pathology. PAD4, also released on NETs, can modify extracellular proteins such as those found in plasma, and therefore could alter the disease profile in sepsis. In this project, we will determine if PAD4 released during sepsis is originating from neutrophils in mice and in patients. With this we will aim to understand the role of NETs in sepsis pathology.