Peptidylarginine deiminase 4 and ADAMTS13 activity in Staphylococcus aureus bacteraemia

Abstract

Staphylococcus aureus infection is associated with increased levels of neutrophil extracellular traps (NETs) and von Willebrand factor (VWF), and with reduced activity of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Peptidylarginine deiminase 4 (PAD4) contributes to NET formation and inactivates ADAMTS13 in vitro . The role of PADs in the dynamics of NETs, VWF and ADAMTS13 has not yet been studied. We thus aimed to assess the longitudinal evolution of NETs, PADs, VWF and ADAMTS13 activity in S. aureus infection. Plasma samples from S. aureus bacteraemia patients were longitudinally collected and analysed for NETs, PAD4/PAD2, VWF and ADAMTS13 activity. Correlation analyses with clinical data were performed. Recombinant PAD4 and S. aureus were assessed in vitro for their potential to modulate ADAMTS13 activity. Sixty-seven patients were included. Plasma levels of NETs, VWF, PAD4 and PAD2 were increased and ADAMTS13 activity was decreased. Levels of PADs were negatively correlated with ADAMTS13 activity. NETs were positively correlated with PADs, and negatively with ADAMTS13 activity. In vitro , recombinant PAD4 but not S. aureus reduced ADAMTS13 activity in plasma. Levels of PAD4 and PAD2 correlate with reduced ADAMTS13 activity, with neutrophils as the likely source of PAD activity in S. aureus bacteraemia. This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.

Citrullination: new tricks for an old mod

“…R. Soc. B 378: 20220235 by Martinod and colleagues probes role of PADI4 and PADI2 in NETs and the regulation of von Willebrand factor and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the innate immune response to bacterial infection, using bacteremia patient samples (Martens et al [19]). Increased understanding of the neutrophil response to bacterial infection may allow improved methods of combating bacteremia in patients while preventing the deleterious consequences of sepsis.…”

“…This work is intriguing, considering the fact that anti-citrullinated protein autoantibodies [ 18 ] consist a key diagnostic and prognostic tool for RA in clinical practice, and may warrant a more careful look at refining the use of such biomarkers to increase the sensitivity of diagnostic tests. A second study by Martinod and colleagues probes role of PADI4 and PADI2 in NETs and the regulation of von Willebrand factor and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the innate immune response to bacterial infection, using bacteremia patient samples (Martens et al [ 19 ]). Increased understanding of the neutrophil response to bacterial infection may allow improved methods of combating bacteremia in patients while preventing the deleterious consequences of sepsis.…”