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Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death.

ABSTRACT: Bacterial invasion of host tissues triggers polymorphonuclear leukocytes to release DNA [neutrophil extracellular traps (NETs)], thereby immobilizing microbes for subsequent clearance by innate defenses including macrophage phagocytosis. We report here that Staphylococcus aureus escapes these defenses by converting NETs to deoxyadenosine, which triggers the caspase-3-mediated death of immune cells. Conversion of NETs to deoxyadenosine requires two enzymes, nuclease and adenosine synthase, that are secreted by S. aureus and are necessary for the exclusion of macrophages from staphylococcal abscesses. Thus, the pathogenesis of S. aureus infections has evolved to anticipate host defenses and to repurpose them for the destruction of the immune system.

SUBMITTER: Thammavongsa V

PROVIDER: S-EPMC4026193 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death.

Thammavongsa Vilasack V Missiakas Dominique M DM Schneewind Olaf O

Science (New York, N.Y.) 20131101 6160

Bacterial invasion of host tissues triggers polymorphonuclear leukocytes to release DNA [neutrophil extracellular traps (NETs)], thereby immobilizing microbes for subsequent clearance by innate defenses including macrophage phagocytosis. We report here that Staphylococcus aureus escapes these defenses by converting NETs to deoxyadenosine, which triggers the caspase-3-mediated death of immune cells. Conversion of NETs to deoxyadenosine requires two enzymes, nuclease and adenosine synthase, that a ...[more]

PMID: 24233725

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Project description:IntroductionNeutrophils can generate extracellular net-like structures by releasing their DNA-histone complexes and antimicrobial peptides, which is called neutrophil extracellular traps (NETs). Various stimuli can induce NET formation. In particular, neutrophils and NET formation are abundant in tumor tissue. This study investigated how cancer cells induce NET formation and whether this NET formation promotes plasma thrombin generation and cancer progression.MethodsInduction of NET formation by a pancreatic cancer cell line (AsPC-1) was assessed by measuring the histone-DNA complex level. The endogenous thrombin potential (ETP) was measured by thrombin generation assay. In vitro migration, invasion, and tubule formation assays were performed. The circulating levels of NET markers and hypercoagulability markers were assessed in 62 patients with pancreatobiliary malignancy and 30 healthy controls.ResultsAsPC-1 significantly induced NET formation in a dose-dependent manner. Conditioned medium (CM) from AsPC-1 also induced NETs. Interestingly, NET-formation was abolished by heat-inactivated CM, but not by lipid-extracted CM, suggesting an important role of protein components. A reactive oxygen species inhibitor did not inhibit cancer cell-induced NET formation, but prostaglandin E1 (PGE1, cyclic adenosine monophosphate inducer) and antithrombin did. NETs significantly increased ETP of normal plasma. Of note, NETs promoted cancer cell migration and invasion as well as angiogenesis, which were inhibited by histone-binding agents (heparin, polysialic acid), a DNA-degrading enzyme, and Toll-like receptor neutralizing antibodies. In patients with pancreatobiliary malignancy, elevated NET markers correlated well with hypercoagulability makers.ConclusionOur findings indicate that cancer cell-induced NET formation enhances both hypercoagulability and cancer progression and suggest that inhibitors of NET formation such as PGE1 and antithrombin can be potential therapeutics to reduce both hypercoagulability and cancer progression.

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Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death.

Publications

Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death.

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