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Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation

Mycobacterium tuberculosis infection generates pulmonary granulomas that consist of a caseous, necrotic core surrounded by an ordered arrangement of macrophages, neutrophils and T cells. This inflammatory pathology is essential for disease transmission and M. tuberculosis has evolved to stimulate in...

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Autores principales: Francis, R J, Butler, R E, Stewart, G R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237235/
https://www.ncbi.nlm.nih.gov/pubmed/25321481
http://dx.doi.org/10.1038/cddis.2014.394
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author Francis, R J
Butler, R E
Stewart, G R
author_facet Francis, R J
Butler, R E
Stewart, G R
author_sort Francis, R J
collection PubMed
description Mycobacterium tuberculosis infection generates pulmonary granulomas that consist of a caseous, necrotic core surrounded by an ordered arrangement of macrophages, neutrophils and T cells. This inflammatory pathology is essential for disease transmission and M. tuberculosis has evolved to stimulate inflammatory granuloma development while simultaneously avoiding destruction by the attracted phagocytes. The most abundant phagocyte in active necrotic granulomas is the neutrophil. Here we show that the ESAT-6 protein secreted by the ESX-1 type VII secretion system causes necrosis of the neutrophils. ESAT-6 induced an intracellular Ca(2+) overload followed by necrosis of phosphatidylserine externalised neutrophils. This necrosis was dependent upon the Ca(2+) activated protease calpain, as pharmacologic inhibition prevented this secondary necrosis. We also observed that the ESAT-6 induced increase in intracellular Ca(2+), stimulated the production of neutrophil extracellular traps characterised by extruded DNA and myeloperoxidase. Thus we conclude that ESAT-6 has a leukocidin function, which may facilitate bacterial avoidance of the antimicrobial action of the neutrophil while contributing to the maintenance of inflammation and necrotic pathology necessary for granuloma formation and TB transmission.
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spelling pubmed-42372352014-11-26 Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation Francis, R J Butler, R E Stewart, G R Cell Death Dis Original Article Mycobacterium tuberculosis infection generates pulmonary granulomas that consist of a caseous, necrotic core surrounded by an ordered arrangement of macrophages, neutrophils and T cells. This inflammatory pathology is essential for disease transmission and M. tuberculosis has evolved to stimulate inflammatory granuloma development while simultaneously avoiding destruction by the attracted phagocytes. The most abundant phagocyte in active necrotic granulomas is the neutrophil. Here we show that the ESAT-6 protein secreted by the ESX-1 type VII secretion system causes necrosis of the neutrophils. ESAT-6 induced an intracellular Ca(2+) overload followed by necrosis of phosphatidylserine externalised neutrophils. This necrosis was dependent upon the Ca(2+) activated protease calpain, as pharmacologic inhibition prevented this secondary necrosis. We also observed that the ESAT-6 induced increase in intracellular Ca(2+), stimulated the production of neutrophil extracellular traps characterised by extruded DNA and myeloperoxidase. Thus we conclude that ESAT-6 has a leukocidin function, which may facilitate bacterial avoidance of the antimicrobial action of the neutrophil while contributing to the maintenance of inflammation and necrotic pathology necessary for granuloma formation and TB transmission. Nature Publishing Group 2014-10 2014-10-16 /pmc/articles/PMC4237235/ /pubmed/25321481 http://dx.doi.org/10.1038/cddis.2014.394 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Francis, R J
Butler, R E
Stewart, G R
Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title_full Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title_fullStr Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title_full_unstemmed Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title_short Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca(2+) influx, necrosis and neutrophil extracellular trap formation
title_sort mycobacterium tuberculosis esat-6 is a leukocidin causing ca(2+) influx, necrosis and neutrophil extracellular trap formation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237235/
https://www.ncbi.nlm.nih.gov/pubmed/25321481
http://dx.doi.org/10.1038/cddis.2014.394
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