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Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia

Francisella tularensis(Ft) is a highly virulent, intracellular Gram-negative bacterial pathogen. Acute Ft infection by aerosol route causes pneumonic tularemia, characterized by nodular hemorrhagic lesions, neutrophil-predominant influx, necrotic debris, fibrin deposition, and severe alveolitis. Ft...

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Autores principales: Pulavendran, Sivasami, Prasanthi, Maram, Ramachandran, Akhilesh, Grant, Rezabek, Snider, Timothy A., Chow, Vincent T. K., Malayer, Jerry R., Teluguakula, Narasaraju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193117/
https://www.ncbi.nlm.nih.gov/pubmed/32391009
http://dx.doi.org/10.3389/fimmu.2020.00679
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author Pulavendran, Sivasami
Prasanthi, Maram
Ramachandran, Akhilesh
Grant, Rezabek
Snider, Timothy A.
Chow, Vincent T. K.
Malayer, Jerry R.
Teluguakula, Narasaraju
author_facet Pulavendran, Sivasami
Prasanthi, Maram
Ramachandran, Akhilesh
Grant, Rezabek
Snider, Timothy A.
Chow, Vincent T. K.
Malayer, Jerry R.
Teluguakula, Narasaraju
author_sort Pulavendran, Sivasami
collection PubMed
description Francisella tularensis(Ft) is a highly virulent, intracellular Gram-negative bacterial pathogen. Acute Ft infection by aerosol route causes pneumonic tularemia, characterized by nodular hemorrhagic lesions, neutrophil-predominant influx, necrotic debris, fibrin deposition, and severe alveolitis. Ft suppresses activity of neutrophils by impairing their respiratory burst and phagocytic activity. However, the fate of the massive numbers of neutrophils recruited to the infection site is unclear. Here, we show that Ft infection resulted in prominent induction of neutrophil extracellular traps (NETs) within damaged lungs of mice infected with the live attenuated vaccine strain of Ft(Ft-LVS), as well as in the lungs of domestic cats and rabbits naturally infected with Ft. Further, Ft-LVS infection increased lung myeloperoxidase (MPO) activity, which mediates histone protein degradation during NETosis and anchors chromatin scaffolds in NETs. In addition, Ft infection also induced expression of peptidylarginine deiminase 4, an enzyme that causes citrullination of histones during formation of NETs. The released NETs were found largely attached to the alveolar epithelium, and disrupted the thin alveolar epithelial barrier. Furthermore, Ft infection induced a concentration-dependent release of NETs from neutrophils in vitro. Pharmacological blocking of MPO reduced Ft-induced NETs release, whereas addition of H(2)O(2) (a substrate of MPO) significantly augmented NETs release, thus indicating a critical role of MPO in Ft-induced NETs. Although immunofluorescence and electron microscopy revealed that NETs could efficiently trap Ft bacteria, NETs failed to exert bactericidal effects. Taken together, these findings suggest that NETs exacerbate tissue damage in pulmonary Ft infection, and that targeting NETosis may offer novel therapeutic interventions in alleviating Ft-induced tissue damage.
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spelling pubmed-71931172020-05-08 Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia Pulavendran, Sivasami Prasanthi, Maram Ramachandran, Akhilesh Grant, Rezabek Snider, Timothy A. Chow, Vincent T. K. Malayer, Jerry R. Teluguakula, Narasaraju Front Immunol Immunology Francisella tularensis(Ft) is a highly virulent, intracellular Gram-negative bacterial pathogen. Acute Ft infection by aerosol route causes pneumonic tularemia, characterized by nodular hemorrhagic lesions, neutrophil-predominant influx, necrotic debris, fibrin deposition, and severe alveolitis. Ft suppresses activity of neutrophils by impairing their respiratory burst and phagocytic activity. However, the fate of the massive numbers of neutrophils recruited to the infection site is unclear. Here, we show that Ft infection resulted in prominent induction of neutrophil extracellular traps (NETs) within damaged lungs of mice infected with the live attenuated vaccine strain of Ft(Ft-LVS), as well as in the lungs of domestic cats and rabbits naturally infected with Ft. Further, Ft-LVS infection increased lung myeloperoxidase (MPO) activity, which mediates histone protein degradation during NETosis and anchors chromatin scaffolds in NETs. In addition, Ft infection also induced expression of peptidylarginine deiminase 4, an enzyme that causes citrullination of histones during formation of NETs. The released NETs were found largely attached to the alveolar epithelium, and disrupted the thin alveolar epithelial barrier. Furthermore, Ft infection induced a concentration-dependent release of NETs from neutrophils in vitro. Pharmacological blocking of MPO reduced Ft-induced NETs release, whereas addition of H(2)O(2) (a substrate of MPO) significantly augmented NETs release, thus indicating a critical role of MPO in Ft-induced NETs. Although immunofluorescence and electron microscopy revealed that NETs could efficiently trap Ft bacteria, NETs failed to exert bactericidal effects. Taken together, these findings suggest that NETs exacerbate tissue damage in pulmonary Ft infection, and that targeting NETosis may offer novel therapeutic interventions in alleviating Ft-induced tissue damage. Frontiers Media S.A. 2020-04-24 /pmc/articles/PMC7193117/ /pubmed/32391009 http://dx.doi.org/10.3389/fimmu.2020.00679 Text en Copyright © 2020 Pulavendran, Prasanthi, Ramachandran, Grant, Snider, Chow, Malayer and Teluguakula. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pulavendran, Sivasami
Prasanthi, Maram
Ramachandran, Akhilesh
Grant, Rezabek
Snider, Timothy A.
Chow, Vincent T. K.
Malayer, Jerry R.
Teluguakula, Narasaraju
Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title_full Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title_fullStr Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title_full_unstemmed Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title_short Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia
title_sort production of neutrophil extracellular traps contributes to the pathogenesis of francisella tularemia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193117/
https://www.ncbi.nlm.nih.gov/pubmed/32391009
http://dx.doi.org/10.3389/fimmu.2020.00679
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