Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.

Despite considerable research effort, the molecular mechanisms of Mycobacterium tuberculosis (Mtb) virulence remain unclear. Cholesterol oxidase (ChoD), an extracellular enzyme capable of converting cholesterol to its 3-keto-4-ene derivative, cholestenone, has been proposed to play a role in the vir...

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Autores principales:	Magdalena Klink, Marta Brzezinska, Izabela Szulc, Anna Brzostek, Michal Kielbik, Zofia Sulowska, Jaroslaw Dziadek
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/918764a3e5234a7da9e132194adf96da
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spelling	oai:doaj.org-article:918764a3e5234a7da9e132194adf96da2021-11-18T08:56:19ZCholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.1932-620310.1371/journal.pone.0073333https://doaj.org/article/918764a3e5234a7da9e132194adf96da2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24039915/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Despite considerable research effort, the molecular mechanisms of Mycobacterium tuberculosis (Mtb) virulence remain unclear. Cholesterol oxidase (ChoD), an extracellular enzyme capable of converting cholesterol to its 3-keto-4-ene derivative, cholestenone, has been proposed to play a role in the virulence of Mtb. Here, we verified the hypothesis that ChoD is capable of modifying the bactericidal and pro-inflammatory activity of human macrophages. We also sought to determine the contribution of complement receptor 3 (CR3)- and Toll-like receptor 2 (TLR2)-mediated signaling pathways in the development of macrophage responses to Mtb. We found that intracellular replication of an Mtb mutant lacking a functional choD gene (ΔchoD) was less efficient in macrophages than that of the wild-type strain. Blocking CR3 and TLR2 with monoclonal antibodies enhanced survival of ΔchoD inside macrophages. We also showed that, in contrast to wild-type Mtb, the ΔchoD strain induced nitric oxide production in macrophages, an action that depended on the TLR2, but not the CR3, signaling pathway. Both wild-type and mutant strains inhibited the production of reactive oxygen species (ROS), but the ΔchoD strain did so to a significantly lesser extent. Blocking TLR2-mediated signaling abolished the inhibitory effect of wild-type Mtb on ROS production by macrophages. Wild-type Mtb, but not the ΔchoD strain, decreased phorbol myristate acetate-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are involved in both TLR2- and CR3-mediated signaling pathways. Our finding also revealed that the production of interleukin 10 by macrophages was significantly lower in ΔchoD-infected macrophages than in wild-type Mtb-infected macrophages. However, tumor necrosis factor-α production by macrophages was the same after infection with mutant or wild-type strains. In summary, we demonstrate here that ChoD is required for Mtb interference with the TLR2-mediated signaling pathway and subsequent intracellular growth and survival of the pathogen in human macrophages.Magdalena KlinkMarta BrzezinskaIzabela SzulcAnna BrzostekMichal KielbikZofia SulowskaJaroslaw DziadekPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e73333 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Magdalena Klink Marta Brzezinska Izabela Szulc Anna Brzostek Michal Kielbik Zofia Sulowska Jaroslaw Dziadek Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
description	Despite considerable research effort, the molecular mechanisms of Mycobacterium tuberculosis (Mtb) virulence remain unclear. Cholesterol oxidase (ChoD), an extracellular enzyme capable of converting cholesterol to its 3-keto-4-ene derivative, cholestenone, has been proposed to play a role in the virulence of Mtb. Here, we verified the hypothesis that ChoD is capable of modifying the bactericidal and pro-inflammatory activity of human macrophages. We also sought to determine the contribution of complement receptor 3 (CR3)- and Toll-like receptor 2 (TLR2)-mediated signaling pathways in the development of macrophage responses to Mtb. We found that intracellular replication of an Mtb mutant lacking a functional choD gene (ΔchoD) was less efficient in macrophages than that of the wild-type strain. Blocking CR3 and TLR2 with monoclonal antibodies enhanced survival of ΔchoD inside macrophages. We also showed that, in contrast to wild-type Mtb, the ΔchoD strain induced nitric oxide production in macrophages, an action that depended on the TLR2, but not the CR3, signaling pathway. Both wild-type and mutant strains inhibited the production of reactive oxygen species (ROS), but the ΔchoD strain did so to a significantly lesser extent. Blocking TLR2-mediated signaling abolished the inhibitory effect of wild-type Mtb on ROS production by macrophages. Wild-type Mtb, but not the ΔchoD strain, decreased phorbol myristate acetate-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are involved in both TLR2- and CR3-mediated signaling pathways. Our finding also revealed that the production of interleukin 10 by macrophages was significantly lower in ΔchoD-infected macrophages than in wild-type Mtb-infected macrophages. However, tumor necrosis factor-α production by macrophages was the same after infection with mutant or wild-type strains. In summary, we demonstrate here that ChoD is required for Mtb interference with the TLR2-mediated signaling pathway and subsequent intracellular growth and survival of the pathogen in human macrophages.
format	article
author	Magdalena Klink Marta Brzezinska Izabela Szulc Anna Brzostek Michal Kielbik Zofia Sulowska Jaroslaw Dziadek
author_facet	Magdalena Klink Marta Brzezinska Izabela Szulc Anna Brzostek Michal Kielbik Zofia Sulowska Jaroslaw Dziadek
author_sort	Magdalena Klink
title	Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
title_short	Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
title_full	Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
title_fullStr	Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
title_full_unstemmed	Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.
title_sort	cholesterol oxidase is indispensable in the pathogenesis of mycobacterium tuberculosis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/918764a3e5234a7da9e132194adf96da
work_keys_str_mv	AT magdalenaklink cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT martabrzezinska cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT izabelaszulc cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT annabrzostek cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT michalkielbik cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT zofiasulowska cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis AT jaroslawdziadek cholesteroloxidaseisindispensableinthepathogenesisofmycobacteriumtuberculosis
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Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis.

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