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Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics m...

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Autores principales: Linnemann, Lara C., Schaible, Ulrich E., Dallenga, Tobias K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910451/
https://www.ncbi.nlm.nih.gov/pubmed/35269694
http://dx.doi.org/10.3390/ijms23052554
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author Linnemann, Lara C.
Schaible, Ulrich E.
Dallenga, Tobias K.
author_facet Linnemann, Lara C.
Schaible, Ulrich E.
Dallenga, Tobias K.
author_sort Linnemann, Lara C.
collection PubMed
description Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.
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spelling pubmed-89104512022-03-11 Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo Linnemann, Lara C. Schaible, Ulrich E. Dallenga, Tobias K. Int J Mol Sci Article Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo. MDPI 2022-02-25 /pmc/articles/PMC8910451/ /pubmed/35269694 http://dx.doi.org/10.3390/ijms23052554 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Linnemann, Lara C.
Schaible, Ulrich E.
Dallenga, Tobias K.
Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title_full Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title_fullStr Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title_full_unstemmed Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title_short Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
title_sort evaluation of myeloperoxidase as target for host-directed therapy in tuberculosis in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910451/
https://www.ncbi.nlm.nih.gov/pubmed/35269694
http://dx.doi.org/10.3390/ijms23052554
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