Dataset Information

Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis.

ABSTRACT:

Background

Infections with parasites of the Leishmania donovani complex result in clinical outcomes that range from asymptomatic infection to severe and fatal visceral leishmaniasis (VL). Neutrophils are major players of the immune response against Leishmania, but their contribution to distinct states of infection is unknown. Gene expression data suggest the activation of the NETosis pathway during human visceral leishmaniasis. Thus, we conducted an exploratory study to evaluate NET-related molecules in retrospective sera from VL patients, asymptomatic individuals and uninfected endemic controls.

Results

We demonstrate that VL patients and asymptomatic individuals exhibit differential regulation of molecules associated with neutrophil extracellular traps (NET). These differences were observed at the transcriptional level of genes encoding NET-associated proteins; in quantifications of cell free DNA and metalloproteinase 9; and in enzymatic activity of DNAse and elastase. Moreover, multivariate analysis resulted in class-specific signatures, and ROC curves demonstrate the ability of these molecules in discriminating asymptomatic infection from uninfected controls.

Conclusion

Molecules that are associated with NETs are differentially regulated between distinct states of infection with L. infantum, suggesting that NETs might have distinct roles depending on the clinical status of infection. Although unlikely to be exclusive for VL, these signatures can be useful to better characterize asymptomatic infections in endemic regions of this disease.

SUBMITTER: Gardinassi LG

PROVIDER: S-EPMC5460406 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis.

Gardinassi Luiz Gustavo LG DeSouza-Vieira Thiago S TS da Silva Naila O NO Garcia Gustavo R GR Borges Valéria M VM Campos Roseane N S RNS de Almeida Roque P RP de Miranda Santos Isabel K F IKF Saraiva Elvira M EM

Parasites & vectors 20170606 1

<h4>Background</h4>Infections with parasites of the Leishmania donovani complex result in clinical outcomes that range from asymptomatic infection to severe and fatal visceral leishmaniasis (VL). Neutrophils are major players of the immune response against Leishmania, but their contribution to distinct states of infection is unknown. Gene expression data suggest the activation of the NETosis pathway during human visceral leishmaniasis. Thus, we conducted an exploratory study to evaluate NET-rela ...[more]

PMID: 28583201

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Project description:BackgroundPolymorphonuclear neutrophils (PMNs) are the main effector cells in inflammatory responses and play multiple roles in thyroid cancer (TC). PMNs contain and release a plethora of mediators, including granular enzymes [e.g., myeloperoxidase (MPO), pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9)], and neutrophil extracellular traps (NETs). The aim of this study was to evaluate NETs and neutrophil-derived mediators as possible biomarkers in TC patients.Methods20 patients with differentiated thyroid cancer (DTC), 26 patients with dedifferentiated thyroid cancer (De-DTC), 26 patients with multinodular goiter (MNG) and 22 healthy controls (HCs) were recruited. Serum concentrations of free DNA (dsDNA), nucleosomes, citrullinated histone H3 (CitH3) and MPO-DNA complexes were evaluated as NET biomarkers. Neutrophil-related mediators such as MPO, PTX3, MMP-9, CXCL8, and granulocyte-monocyte colony-stimulating factor (GM-CSF) were measured by ELISA.ResultsSerum levels of all four NET biomarkers were increased in DeDTC patients compared to HCs. CitH3 serum levels were selectively increased in both DeDTC and DTC patients compared to HCs and MNG patients. MPO-DNA complexes and nucleosomes were selectively increased only in DeDTC patients compared to HCs and MNG patients. Moreover, MPO-DNA complexes were selectively increased in DeDTC patients compared to DTC patients also. MPO circulating levels were selectively increased in the DeDTC patient subgroup compared to HCs. Circulating levels of PTX3, MMP-9 and GM-CSF were increased in DTC and DeDTC patients compared to HCs. Nucleosomes positively correlated with dsDNA, CitH3, MPO and CXCL8. MPO-DNA complexes positively correlated with dsDNA, CitH3, CXCL8, MPO and nucleosome levels. Moreover, three out of the four NET biomarkers (i.e., dsDNA, nucleosomes and MPO-DNA complexes) were increased in elderly patients compared to young patients and in patients with metastatic disease at diagnosis compared to non metastatic patients. Nucleosomes were higher in males compared to females.ConclusionMPO-DNA complexes, nucleosomes and, to some extent, CitH3 levels seem to correlate with malignancy and severity of progressive TC. Moreover, serum concentrations of PMN-related mediators (MPO, PTX3, GM-CSF) were increased in TCs compared to MNG and HCs.

Project description:Neutrophil extracellular traps (NETs), a key component of early defense against microbial infection, are also associated with tissue injury. NET composition has been reported to vary with some disease states, but the composition and variability of NETs across many healthy subjects provide a critical comparison that has not been well investigated. We evaluated NETs from twelve healthy subjects of varying ages isolated from multiple blood draws over a three-and-one-half-year period to delineate the variability in extracellular DNA, protein, enzymatic activities, and susceptibility to protease inhibitors. We calculated correlations for NET constituents and loss of human bronchial epithelial barrier integrity, measured by transepithelial electrical resistance, after NET exposure. We found that although there was some variability within the same subject over time, the mean NET total DNA, dsDNA, protein, LDH, neutrophil elastase (NE), and proteinase 3 (PR3) in isolated NETs were consistent across subjects. NET serine protease activity varied considerably within the same donor from day to day. The mean NET cathepsin G and MPO were significantly different across donors. IL-8 > IL-1RA > G-CSF were the most abundant cytokines in NETs. There was no significant difference in the mean concentration or variability of IL-8, IL-1RA, G-CSF, IL-1α, IL-1β, or TNF-α in different subjects' NETs. NET DNA concentration was correlated with increased NET neutrophil elastase activity and higher NET IL-1RA concentrations. The mean reduction in protease activity by protease inhibitors was significantly different across donors. NET DNA concentration correlated best with reductions in the barrier integrity of human bronchial epithelia. Defining NET concentration by DNA content correlates with other NET components and reductions in NET-driven epithelial barrier dysfunction, suggesting DNA is a reasonable surrogate measurement for these complex structures in healthy subjects.

Dataset Information

Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis.

Background

Results

Conclusion

Publications

Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis.

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