2. Academic Validation
  3. Panton-Valentine leukocidin-induced neutrophil extracellular traps lack antimicrobial activity and are readily induced in patients with recurrent PVL+-Staphylococcus aureus infections

Panton-Valentine leukocidin-induced neutrophil extracellular traps lack antimicrobial activity and are readily induced in patients with recurrent PVL+-Staphylococcus aureus infections

  • J Leukoc Biol. 2023 Nov 7:qiad137. doi: 10.1093/jleuko/qiad137.
Hina Jhelum 1,  Dora Čerina 1,  C J Harbort 1,  Andreas Lindner 2,  Leif Gunnar Hanitsch 3,  Rasmus Leistner 4,  Jennyver-Tabea Schröder 5,  Horst von Bernuth 6 7 8 9,  Miriam Songa Stegemann 10,  Mariana Schürmann 10,  Arturo Zychlinsky 1,  Renate Krüger 6,  Gerben Marsman 1
Affiliations

Affiliations

  • 1 Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
  • 2 Institute of Tropical Medicine and International Health, Charité, Universitätsmedizin Berlin, Berlin, Germany.
  • 3 Department of Medical Immunology, Charité, Universitätsmedizin Berlin, Berlin, Germany.
  • 4 Institute of Hygiene and Environmental Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
  • 5 Department of Pediatric Surgery, Charité, Universitätsmedizin Berlin, Berlin, Germany.
  • 6 Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
  • 7 Department of Immunology, Labor Berlin GmbH, Berlin, Germany.
  • 8 Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany.
  • 9 Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
  • 10 Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
PMID: 37943843 DOI: 10.1093/jleuko/qiad137
Abstract

Staphylococcus aureus (S. aureus) strains that produce the toxin Panton-Valentine leukocidin (PVL; PVL-SA) frequently cause recurrent skin and soft tissue infections (SSTI). PVL binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps, but the pathomechanism has not been extensively studied. Furthermore, it is unclear why some individuals colonized with PVL-SA suffer from recurring infections whereas Others are asymptomatic. We thus aimed to (a) investigate how PVL exerts its pathogenicity on neutrophils and (b) identify factors that could help to explain the predisposition of patients with recurring infections. We provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and Reactive Oxygen Species (ROS) production. Moreover, through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), Elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, and as such they were unable to kill S. aureus. Furthermore, we found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to be killed at a low PVL concentration than control neutrophils. Neutrophils from patients that suffer from recurring PVL-positive infections may thus be more sensitive to PVL-induced NET formation, which might impair their ability to combat the Infection.

Keywords

Neutrophils; Panton-Valentine leukocidin; Staphylococcus aureus; neutrophil extracellular traps; toxin.

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