Underlying mechanisms of sepsis

Sepsis is an inflammatory condition caused by bacteria such as Staphylococcus aureus and has potentially life-threatening consequences as key organs may be affected. The emergence of methicillin-resistant S. aureus (MRSA) hampers the effective treatment of blood infection (bacteraemia), thereby posing a serious hospital-associated health threat.

Insight into the immune mechanism associated with sepsis involves neutrophils that kill bacteria through phagocytosis, release of antimicrobial proteins or through neutrophil extracellular traps (NETs). NETs function to trap and kill bacteria but they can induce severe damage to the lung and the liver endothelium if they persist in the vasculature. NETs consist of DNA, histones and various enzymes (peptidyl arginine deiminase 4, neutrophil elastase, matrix metalloproteinase-9).

To understand how the composition of NETs may lead to the killing of bystander cells, the EU-funded NET-INJURY-IN-SEPSIS (Endothelial injury during sepsis: do NET-attached proteases participate in this process?) project utilised intravital microscopy to observe in vivo events. In a mouse model of MRSA infection, scientists looked at the liver and how the formation of NET structures impacted on liver morphology and the induction of sepsis.

Project members conclusively demonstrated that neutrophil elastase participated in NET formation and was indeed implicated in sepsis-mediated liver pathology. Moreover, genetic deficiency or pharmacological inhibition of neutrophil elastase prevented liver damage.

In another part of the study, researchers investigated how treatment with DNAse, which dissolves the DNA backbone of NETs, will affect NET persistence. Results indicated that DNAse alone was insufficient for preventing liver damage as it could not remove all NET constituents.

Taken together, the findings of the present work provided novel insight into the mechanism of sepsis-related inflammation and underscore the importance of NETs in disease pathology. They also suggest potential therapeutic interventions that could be used for other inflammatory conditions associated with NETs.