Neutrophil extracellular traps: Casting the NET over pathogenesis

Department of Bacteriology, Swedish Institute for Infectious Disease Control Nobelsväg 18, SE-171 82 Solna, Solna, Sweden.
Current Opinion in Microbiology (Impact Factor: 5.9). 03/2007; 10(1):52-6. DOI: 10.1016/j.mib.2006.12.005
Source: PubMed


Neutrophil extracellular traps (NETs) are considered to be part of the human innate immunity because they trap and kill pathogens. NETs are formed by activated neutrophils and consist of a DNA backbone with embedded antimicrobial peptides and enzymes. They are involved in host defense during pneumococcal pneumonia, streptococcal necrotizing fasciitis, appendicitis and insemination. Recently, bacterial virulence factors that counteract NETs have been identified. These include the degradation of the NET-backbone by DNases enabling the liberation of bacteria from NETs, as well as capsule formation, which reduces bacterial trapping. Furthermore, pathogens can resist NET-mediated killing by adding positive charge to their cell surface.

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    • "survival of GAS when entangled in neutrophil extracellular traps (NETs) (Buchanan et al., 2006; de Buhr et al., 2014; Wartha et al., 2007). The interaction between GAS phage and non-phage genes and their products is an evolving field that is bound to shed important new light on the pathogenesis of GAS infections. "
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    ABSTRACT: Streptococcus pyogenes (group A Streptococcus; GAS) is a strict human pathogen with a very high prevalence worldwide. This review highlights the genetic organization of the species and the important ecological considerations that impact its evolution. Recent advances are presented on the topics of molecular epidemiology, population biology, molecular basis for genetic change, genome structure and genetic flux, phylogenomics and closely related streptococcal species, and the long- and short-term evolution of GAS. The application of whole genome sequence data to addressing key biological questions is discussed.
    Full-text · Article · Oct 2014 · Infection Genetics and Evolution
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    • "Deficiency of the CTSC activity in tested fluids was associated with the absence or severe reduction of activity of neutrophil serine proteases, such as NE and PR3. Thus, the inflammatory response to pathogenic bacteria must be disturbed in PLS patients since neutrophil serine proteases activate gingival fibroblasts to produce inflammatory cytokines [31] and are components of neutrophil extracellular traps which trap and kill pathogens [32]. Further, reactive oxygen species generation and MPO activity is not sufficient to kill microbes and proteases are primarily responsible for the destruction of phagocytosed bacteria [33]. "
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    ABSTRACT: Background Loss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). PLS neutrophils lack serine protease activity essential for cathelicidin LL-37 generation from hCAP18 precursor.AimWe hypothesized that a local deficiency of LL-37 in the infected periodontium is mainly responsible for one of the clinical hallmark of PLS: severe periodontitis already in early childhood.Methods To confirm this effect, we compared the level of neutrophil-derived enzymes and antimicrobial peptides in gingival crevicular fluid (GCF) and saliva from PLS, aggressive and chronic periodontitis patients.ResultsAlthough neutrophil numbers in GCF were present at the same level in all periodontitis groups, LL-37 was totally absent in GCF from PLS patients despite the large amounts of its precursor, hCAP18. The absence of LL-37 in PLS patients coincided with the deficiency of both cathepsin C and protease 3 activities. The presence of other neutrophilic anti-microbial peptides in GCF from PLS patients, such as alpha-defensins, were comparable to that found in chronic periodontitis. In PLS microbial analysis revealed a high prevalence of Aggregatibacter actinomycetemcomitans infection. Most strains were susceptible to killing by LL-37.Conclusions Collectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease.
    Full-text · Article · Sep 2014 · Orphanet Journal of Rare Diseases
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    • "NET were first described by Brinkmann et al. [14] showing that PMN are capable to release granular proteins and chromatin forming thin extracellular fibers that bind Gram-positive and-negative bacteria [15], [16], [17]. The major structural component of NETs is DNA which is studded with antimicrobial proteins composed of nuclear histones, granula-derived neutrophil elastase (NE), myeloperoxidase (MPO), lactoferrin, and gelatinase [14], [18], [19]. Overall, NET formation has been described as a novel form of cell death called ETosis which is distinct from apoptosis, autophagy and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase [17], [20]. "
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    ABSTRACT: Besnoitia besnoiti infection in cattle is an important emerging protozoan disease in Europe causing economic losses and severe clinical signs, such as generalized dermatitis, orchitis, and vulvitis in affected animals. Neutrophil extracellular trap (NET) formation was recently demonstrated as an important effector mechanism of PMN acting against several invading pathogens. In the present study, interactions of bovine PMN with tachyzoites of B. besnoiti were investigated in this respect in vitro. For the demonstration and quantification of NETs, extracellular DNA was stained by Sytox Orange or Pico Green. Fluorescent illustrations as well as scanning electron microscopy analyses (SEM) showed PMN-promoted NET formation rapidly being induced upon contact with B. besnoiti tachyzoites. Co-localization of extracellular DNA with histones, neutrophil elastase (NE) and myeloperoxidase (MPO) in parasite entrapping structures confirmed the classical characteristics of NET. Exposure of PMN to viable, UV attenuated and dead tachyzoites showed a significant induction of NET formation, but even tachyzoite homogenates significantly promoted NETs when compared to negative controls. NETs were abolished by DNase treatment and were reduced after PMN preincubation with NADPH oxidase-, NE- and MPO-inhibitors. Tachyzoite-triggered NET formation led to parasite entrapment as quantitative assays indicated that about one third of tachyzoites were immobilized in NETs. In consequence, tachyzoites were hampered from active invasion of host cells. Thus, transfer of tachyzoites, previously being confronted with PMN, to adequate host cells resulted in significantly reduced infection rates when compared to PMN-free infection controls. To our knowledge, we here report for the first time B. besnoiti-induced NET formation. Our results indicate that PMN-triggered extracellular traps may represent an important effector mechanism of the host early innate immune response against B. besnoiti which may lead to diminishment of initial parasite infection rates during the acute infection phase.
    Full-text · Article · Mar 2014 · PLoS ONE
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