Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps

Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA.
Infection and immunity (Impact Factor: 4.16). 11/2011; 80(2):768-77. DOI: 10.1128/IAI.05730-11
Source: PubMed

ABSTRACT Neutrophils have recently been shown to release DNA-based extracellular traps that contribute to microbicidal killing and have also been implicated in autoimmunity. The role of neutrophil extracellular trap (NET) formation in the host response to nonbacterial pathogens has received much less attention. Here, we show that the protozoan pathogen Toxoplasma gondii elicits the production of NETs from human and mouse neutrophils. Tachyzoites of each of the three major parasite strain types were efficiently entrapped within NETs, resulting in decreased parasite viability. We also show that Toxoplasma activates a MEK-extracellular signal-regulated kinase (ERK) pathway in neutrophils and that the inhibition of this pathway leads to decreased NET formation. To determine if Toxoplasma induced NET formation in vivo, we employed a mouse intranasal infection model. We found that the administration of tachyzoites by this route induced a rapid tissue recruitment of neutrophils with evidence of extracellular DNA release. Taken together, these data indicate a role for NETs in the host innate response to protozoan infection. We propose that NET formation limits infection by direct microbicidal effects on Toxoplasma as well as by interfering with the ability of the parasite to invade target host cells.

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Available from: Gerald E Duhamel, Aug 23, 2015
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    • "The novel paradigm of innate immunity is that, besides the classical functions of extracellular release of lytic enzymes and phagocytosis, PMN by means of their enzymatic activity , surface receptors and cytoskeleton (Neeli et al., 2009), also have the capacity to release their DNA in response to infectious stimuli (Brinkmann et al., 2004). Thus, at the site of infection PMNs form neutrophil extracellular traps (NETs) that have the ability to bind and kill pathogens outside the cell, such as bacteria (Fuchs et al., 2007; Pilsczek et al., 2010), protozoa (Guimarães-Costa et al., 2009; Wardini et al., 2010; Abdallah et al., 2012), or yeast (Urban et al., 2006, 2009). In addition, as reviewed by Brinkmann and Zychlinsky (2012), not only infectious agents, but also many physiological inducers of NET formation have been reported. "
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    ABSTRACT: Besides the classical functions, neutrophils (PMNs) are able to release DNA in response to infectious stimuli, forming neutrophil extracellular traps (NETs) and killing pathogens. The pathogenesis of endometritis in the mare is not completely understood. The aim was to evaluate the in vitro capacity of equine PMNs to secrete NETs by chemical activation, or stimulated with Streptococcus equi subspecies zooepidemicus (Szoo), Escherichia coli (Ecoli) or Staphylococcus capitis (Scap) strains obtained from mares with endometritis. Ex vivo endometrial mucus from mares with bacterial endometritis were evaluated for the presence of NETs. Equine blood PMNs were used either without or with stimulation by phorbol-myristate-acetate (PMA), a strong inducer of NETs, for 1–3 h. To evaluate PMN ability to produce NETs when phagocytosis was impaired, the phagocytosis inhibitor cytochalasin (Cyt) was added after PMA. After the addition of bacteria, a subsequent 1-h incubation was carried out in seven groups. NETs were visualized by 4‘,6-diamidino-2-phenylindole (DAPI) and anti-histone. Ex vivo samples were immunostained for myeloperoxidase and neutrophil elastase. A 3-h incubation period of PMN + PMA increased NETs (p < 0.05). Bacteria + 25 nM PMA and bacteria + PMA + Cyt increased NETs (p < 0.05). Szoo induced fewer NETs than Ecoli or Scap (p < 0.05). Ex vivo NETs were present in mares with endometritis. Scanning electron microscopy showed the spread of NETs formed by smooth fibers and globules that can be aggregated in thick bundles. Formation of NETs and the subsequent entanglement of bacteria suggest that equine NETs might be a complementary mechanism in fighting some of the bacteria causing endometritis in the mare.
    Journal of Reproductive Immunology 08/2014; 106. DOI:10.1016/j.jri.2014.08.003 · 2.37 Impact Factor
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    • "NETs also modulate protozoan infections, trapping and killing Leishmania amazonensis promastigotes [18] while the promastigotes of Leishmania donovani are captured but not killed [19]. The protozoan parasite Toxoplasma gondii induces human and mouse neutrophils to release NETs that have microbicidal effects [20]. Yet, a role for NETs during parasitic helminth infections has not been described. "
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    Microbes and Infection 06/2014; 16(6):502-511. DOI:10.1016/j.micinf.2014.02.012 · 2.73 Impact Factor
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    • "Interestingly, in a presumably homogenous population of isolated neutrophils, only a small fraction of cells performs NETosis despite the fact that all cells are stimulated by the same trigger or touch the same stimulating pathogenic surface (Bruns et al, 2010). Thrown out NETs form a tight contact with pathogens as diverse as fungi (Fig 1) (Urban et al, 2006; Hasenberg et al, 2011b), bacteria (Beiter et al, 2006) and protozoa (Guimaraes-Costa et al, 2009; Abi Abdallah et al, 2012), during which many of the pathogens are also killed. However, as Mocsai (2013) recently pointed out, despite the massive response of the field towards this initial discovery and while the general concept of NETs as means to immobilize pathogens is now accepted, their role and importance in pathogen killing are still controversial (Menegazzi et al, 2012; Nauseef, 2012). "
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