title: Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets.
abstract: BACKGROUND
  Endocarditis-inducing streptococci form multilayered biofilms in complex with aggregated platelets on injured heart valves, but the host factors that interconnect and entrap these bacteria-platelet aggregates to promote vegetation formation were unclear.
  
  
  RESULTS
  In a Streptococcus mutans endocarditis rat model, we identified layers of neutrophil extracellular traps interconnecting and entrapping bacteria-platelet aggregates inside vegetation that could be reduced significantly in size along with diminished colonizing bacteria by prophylaxis with intravascular DNase I alone. The combination of activated platelets and specific immunoglobulin G-adsorbed bacteria are required to induce the formation of neutrophil extracellular traps through multiple activation pathways. Bacteria play key roles in coordinating the signaling through spleen tyrosine kinase, Src family kinases, phosphatidylinositol-3-kinase, and p38 mitogen-activated protein kinase pathways to upregulate the expression of P-selectin in platelets, while inducing reactive oxygen species-dependent citrullination in the arm of neutrophils. Neutrophil extracellular traps in turn serve as the scaffold to further enhance and entrap bacteria-platelet aggregate formation and expansion.
  
  
  CONCLUSIONS
  Neutrophil extracellular traps promote and expand vegetation formation through enhancing and entrapping bacteria-platelet aggregates on the injured heart valves.
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.).
authors.forename: Chiau-Jing
authors.initials: CJ
authors.lastname: Jung
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.).
authors.forename: Chiou-Yueh
authors.initials: CY
authors.lastname: Yeh
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.).
authors.forename: Ron-Bin
authors.initials: RB
authors.lastname: Hsu
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.).
authors.forename: Chii-Ming
authors.initials: CM
authors.lastname: Lee
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.).
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-J.J., J.-S.C.); Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.Y., J.-S.C.); Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (R.-B.H.); Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-M.L.); and Department of Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (C.-T.S.). chiajs@ntu.edu.tw.
authors.forename: Jean-San
authors.initials: JS
authors.lastname: Chia
mesh_terms: D000818:Animals; D018441:Biofilms / Q000254:growth & development; D001792:Blood Platelets / Q000378:metabolism; D004696:Endocarditis / Q000378:metabolism* / Q000382:microbiology*; D065206:Extracellular Traps / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D010974:Platelet Aggregation; D051381:Rats; D015398:Signal Transduction / Q000276:immunology; D013295:Streptococcus mutans / Q000378:metabolism* / Q000472:pathogenicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D019007:P-Selectin; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: blood platelets; communicable diseases; endocarditis; neutrophils