Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages

Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processe...

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Autores principales:	Cassandra L. R. van Doorn, Sanne A. M. Steenbergen, Kimberley V. Walburg, Tom H. M. Ottenhoff
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	tuberculosis host-directed therapy poly (ADP-ribose) polymerase rucaparib human macrophages Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/fd971f80c2f9413188a89fec032c4eb1
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spelling	oai:doaj.org-article:fd971f80c2f9413188a89fec032c4eb12021-12-01T07:45:41ZPharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages1664-322410.3389/fimmu.2021.712021https://doaj.org/article/fd971f80c2f9413188a89fec032c4eb12021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.712021/fullhttps://doaj.org/toc/1664-3224Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to Mycobacterium tuberculosis (Mtb) is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with Mtb infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against Mtb in human macrophage subsets, the predominant target cell of Mtb. Pharmacological inhibition of PARP decreased intracellular Mtb and MDR-Mtb levels in human macrophages, identifying PARP as a potential target for host-directed therapy against Mtb. PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular Mtb, suggesting a metabolic role in rucaparib-induced control of Mtb. We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.Cassandra L. R. van DoornSanne A. M. SteenbergenKimberley V. WalburgTom H. M. OttenhoffFrontiers Media S.A.articletuberculosishost-directed therapypoly (ADP-ribose) polymeraserucaparibhuman macrophagesImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tuberculosis host-directed therapy poly (ADP-ribose) polymerase rucaparib human macrophages Immunologic diseases. Allergy RC581-607
spellingShingle	tuberculosis host-directed therapy poly (ADP-ribose) polymerase rucaparib human macrophages Immunologic diseases. Allergy RC581-607 Cassandra L. R. van Doorn Sanne A. M. Steenbergen Kimberley V. Walburg Tom H. M. Ottenhoff Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
description	Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to Mycobacterium tuberculosis (Mtb) is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with Mtb infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against Mtb in human macrophage subsets, the predominant target cell of Mtb. Pharmacological inhibition of PARP decreased intracellular Mtb and MDR-Mtb levels in human macrophages, identifying PARP as a potential target for host-directed therapy against Mtb. PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular Mtb, suggesting a metabolic role in rucaparib-induced control of Mtb. We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.
format	article
author	Cassandra L. R. van Doorn Sanne A. M. Steenbergen Kimberley V. Walburg Tom H. M. Ottenhoff
author_facet	Cassandra L. R. van Doorn Sanne A. M. Steenbergen Kimberley V. Walburg Tom H. M. Ottenhoff
author_sort	Cassandra L. R. van Doorn
title	Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
title_short	Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
title_full	Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
title_fullStr	Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
title_full_unstemmed	Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
title_sort	pharmacological poly (adp-ribose) polymerase inhibitors decrease mycobacterium tuberculosis survival in human macrophages
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/fd971f80c2f9413188a89fec032c4eb1
work_keys_str_mv	AT cassandralrvandoorn pharmacologicalpolyadpribosepolymeraseinhibitorsdecreasemycobacteriumtuberculosissurvivalinhumanmacrophages AT sanneamsteenbergen pharmacologicalpolyadpribosepolymeraseinhibitorsdecreasemycobacteriumtuberculosissurvivalinhumanmacrophages AT kimberleyvwalburg pharmacologicalpolyadpribosepolymeraseinhibitorsdecreasemycobacteriumtuberculosissurvivalinhumanmacrophages AT tomhmottenhoff pharmacologicalpolyadpribosepolymeraseinhibitorsdecreasemycobacteriumtuberculosissurvivalinhumanmacrophages
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Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages

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