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Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a...

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Autores principales: Parveen, Sadiya, Shen, Jessica, Lun, Shichun, Zhao, Liang, Alt, Jesse, Koleske, Benjamin, Leone, Robert D., Rais, Rana, Powell, Jonathan D., Murphy, John R., Slusher, Barbara S., Bishai, William R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10654700/
https://www.ncbi.nlm.nih.gov/pubmed/37973991
http://dx.doi.org/10.1038/s41467-023-43304-0
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author Parveen, Sadiya
Shen, Jessica
Lun, Shichun
Zhao, Liang
Alt, Jesse
Koleske, Benjamin
Leone, Robert D.
Rais, Rana
Powell, Jonathan D.
Murphy, John R.
Slusher, Barbara S.
Bishai, William R.
author_facet Parveen, Sadiya
Shen, Jessica
Lun, Shichun
Zhao, Liang
Alt, Jesse
Koleske, Benjamin
Leone, Robert D.
Rais, Rana
Powell, Jonathan D.
Murphy, John R.
Slusher, Barbara S.
Bishai, William R.
author_sort Parveen, Sadiya
collection PubMed
description As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.
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spelling pubmed-106547002023-11-16 Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis Parveen, Sadiya Shen, Jessica Lun, Shichun Zhao, Liang Alt, Jesse Koleske, Benjamin Leone, Robert D. Rais, Rana Powell, Jonathan D. Murphy, John R. Slusher, Barbara S. Bishai, William R. Nat Commun Article As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis. Nature Publishing Group UK 2023-11-16 /pmc/articles/PMC10654700/ /pubmed/37973991 http://dx.doi.org/10.1038/s41467-023-43304-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Parveen, Sadiya
Shen, Jessica
Lun, Shichun
Zhao, Liang
Alt, Jesse
Koleske, Benjamin
Leone, Robert D.
Rais, Rana
Powell, Jonathan D.
Murphy, John R.
Slusher, Barbara S.
Bishai, William R.
Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title_full Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title_fullStr Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title_full_unstemmed Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title_short Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis
title_sort glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against mycobacterium tuberculosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10654700/
https://www.ncbi.nlm.nih.gov/pubmed/37973991
http://dx.doi.org/10.1038/s41467-023-43304-0
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