title: Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates.
abstract: Neutrophils are highly specialized innate effector cells that have evolved for killing of pathogens. Human neonates have a common multifactorial syndrome of neutrophil dysfunction that is incompletely characterized and contributes to sepsis and other severe infectious complications. We identified a novel defect in the antibacterial defenses of neonates: inability to form neutrophil extracellular traps (NETs). NETs are lattices of extracellular DNA, chromatin, and antibacterial proteins that mediate extracellular killing of microorganisms and are thought to form via a unique death pathway signaled by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-generated reactive oxygen species (ROS). We found that neutrophils from term and preterm infants fail to form NETs when activated by inflammatory agonists-in contrast to leukocytes from healthy adults. The deficiency in NET formation is paralleled by a previously unrecognized deficit in extracellular bacterial killing. Generation of ROSs did not complement the defect in NET formation by neonatal neutrophils, as it did in adult cells with inactivated NADPH oxidase, demonstrating that ROSs are necessary but not sufficient signaling intermediaries and identifying a deficiency in linked or downstream pathways in neonatal leukocytes. Impaired NET formation may be a critical facet of a common developmental immunodeficiency that predisposes newborn infants to infection.
authors.affiliation: Department of Pediatrics/Neonatology, University of Utah, Salt Lake City, USA. christian.yost@hmbg.utah.edu
authors.forename: Christian C
authors.initials: CC
authors.lastname: Yost
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cody
authors.forename: Estelle S
authors.initials: ES
authors.lastname: Harris
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Thornton
authors.forename: Alison M
authors.initials: AM
authors.lastname: McInturff
authors.forename: Mark L
authors.initials: ML
authors.lastname: Martinez
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Chandler
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Rodesch
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Albertine
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Petti
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
mesh_terms: D000328:Adult; D000375:Aging / Q000276:immunology; D001770:Blood Bactericidal Activity; D002843:Chromatin / Q000502:physiology; D004247:DNA / Q000502:physiology; D004198:Disease Susceptibility; D005110:Extracellular Space; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn / Q000276:immunology*; D007234:Infant, Premature / Q000276:immunology*; D007239:Infections / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D046911:Macromolecular Substances / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics; D016897:Respiratory Burst; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002843:Chromatin; D008070:Lipopolysaccharides; D046911:Macromolecular Substances; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; C039351:platelet activating factor receptor; D004247:DNA