Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN.
Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exoge...
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ftdoajarticles:oai:doaj.org/article:dd93650d7e5543128aca28468e674884 2023-05-15T15:14:59+02:00 Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. Kathryn Zavala Carter A Gottlieb Rosane M Teles John S Adams Martin Hewison Robert L Modlin Philip T Liu 2018-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006815 https://doaj.org/article/dd93650d7e5543128aca28468e674884 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC6177120?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006815 https://doaj.org/article/dd93650d7e5543128aca28468e674884 PLoS Neglected Tropical Diseases, Vol 12, Iss 10, p e0006815 (2018) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2018 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006815 2022-12-31T13:29:20Z Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 12 10 e0006815 |
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Directory of Open Access Journals: DOAJ Articles |
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language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Kathryn Zavala Carter A Gottlieb Rosane M Teles John S Adams Martin Hewison Robert L Modlin Philip T Liu Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN. |
format |
Article in Journal/Newspaper |
author |
Kathryn Zavala Carter A Gottlieb Rosane M Teles John S Adams Martin Hewison Robert L Modlin Philip T Liu |
author_facet |
Kathryn Zavala Carter A Gottlieb Rosane M Teles John S Adams Martin Hewison Robert L Modlin Philip T Liu |
author_sort |
Kathryn Zavala |
title |
Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
title_short |
Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
title_full |
Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
title_fullStr |
Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
title_full_unstemmed |
Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN. |
title_sort |
intrinsic activation of the vitamin d antimicrobial pathway by m. leprae infection is inhibited by type i ifn. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2018 |
url |
https://doi.org/10.1371/journal.pntd.0006815 https://doaj.org/article/dd93650d7e5543128aca28468e674884 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 12, Iss 10, p e0006815 (2018) |
op_relation |
http://europepmc.org/articles/PMC6177120?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006815 https://doaj.org/article/dd93650d7e5543128aca28468e674884 |
op_doi |
https://doi.org/10.1371/journal.pntd.0006815 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
12 |
container_issue |
10 |
container_start_page |
e0006815 |
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1766345371516141568 |