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Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages

BACKGROUND: Macrophages infected with Mycobacterium tuberculosis (M.tb) are known to be refractory to IFN-γ stimulation. Previous studies have shown that M.tb express components such as the 19-kDa lipoprotein and peptidoglycan that can bind to macrophage receptors including the Toll-like receptor 2...

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Autores principales: Singh, Prachi P., LeMaire, Christopher, Tan, John C., Zeng, Erliang, Schorey, Jeffery S.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077381/
https://www.ncbi.nlm.nih.gov/pubmed/21533172
http://dx.doi.org/10.1371/journal.pone.0018564
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author Singh, Prachi P.
LeMaire, Christopher
Tan, John C.
Zeng, Erliang
Schorey, Jeffery S.
author_facet Singh, Prachi P.
LeMaire, Christopher
Tan, John C.
Zeng, Erliang
Schorey, Jeffery S.
author_sort Singh, Prachi P.
collection PubMed
description BACKGROUND: Macrophages infected with Mycobacterium tuberculosis (M.tb) are known to be refractory to IFN-γ stimulation. Previous studies have shown that M.tb express components such as the 19-kDa lipoprotein and peptidoglycan that can bind to macrophage receptors including the Toll-like receptor 2 resulting in the loss in IFN-γresponsiveness. However, it is unclear whether this effect is limited to infected macrophages. We have previously shown that M.tb-infected macrophages release exosomes which are 30–100 nm membrane bound vesicles of endosomal origin that function in intercellular communication. These exosomes contain mycobacterial components including the 19-kDa lipoprotein and therefore we hypothesized that macrophages exposed to exosomes may show limited response to IFN-γ stimulation. METHODOLOGY/PRINCIPAL FINDINGS: Exosomes were isolated from resting as well as M.tb-infected RAW264.7 macrophages. Mouse bone marrow-derived macrophages (BMMØ) were treated with exosomes +/− IFN-γ. Cells were harvested and analyzed for suppression of IFN-γ responsive genes by flow cytometry and real time PCR. We found that exosomes derived from M.tb H37Rv-infected but not from uninfected macrophages inhibited IFN-γ induced MHC class II and CD64 expression on BMMØ. This inhibition was only partially dependent on the presence of lipoproteins but completely dependent on TLR2 and MyD88. The exosomes isolated from infected cells did not inhibit STAT1 Tyrosine phosphorylation but down-regulated IFN-γ induced expression of the class II major histocompatibity complex transactivator; a key regulator of class II MHC expression. Microarray studies showed that subsets of genes induced by IFN-γ were inhibited by exosomes from H37Rv-infeced cells including genes involved in antigen presentation. Moreover, this set of genes partially overlapped with the IFN-γ-induced genes inhibited by H37Rv infection. CONCLUSIONS: Our study suggests that exosomes, as carriers of M.tb pathogen associated molecular patterns (PAMPs), may provide a mechanism by which M.tb may exert its suppression of a host immune response beyond the infected cell.
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spelling pubmed-30773812011-04-29 Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages Singh, Prachi P. LeMaire, Christopher Tan, John C. Zeng, Erliang Schorey, Jeffery S. PLoS One Research Article BACKGROUND: Macrophages infected with Mycobacterium tuberculosis (M.tb) are known to be refractory to IFN-γ stimulation. Previous studies have shown that M.tb express components such as the 19-kDa lipoprotein and peptidoglycan that can bind to macrophage receptors including the Toll-like receptor 2 resulting in the loss in IFN-γresponsiveness. However, it is unclear whether this effect is limited to infected macrophages. We have previously shown that M.tb-infected macrophages release exosomes which are 30–100 nm membrane bound vesicles of endosomal origin that function in intercellular communication. These exosomes contain mycobacterial components including the 19-kDa lipoprotein and therefore we hypothesized that macrophages exposed to exosomes may show limited response to IFN-γ stimulation. METHODOLOGY/PRINCIPAL FINDINGS: Exosomes were isolated from resting as well as M.tb-infected RAW264.7 macrophages. Mouse bone marrow-derived macrophages (BMMØ) were treated with exosomes +/− IFN-γ. Cells were harvested and analyzed for suppression of IFN-γ responsive genes by flow cytometry and real time PCR. We found that exosomes derived from M.tb H37Rv-infected but not from uninfected macrophages inhibited IFN-γ induced MHC class II and CD64 expression on BMMØ. This inhibition was only partially dependent on the presence of lipoproteins but completely dependent on TLR2 and MyD88. The exosomes isolated from infected cells did not inhibit STAT1 Tyrosine phosphorylation but down-regulated IFN-γ induced expression of the class II major histocompatibity complex transactivator; a key regulator of class II MHC expression. Microarray studies showed that subsets of genes induced by IFN-γ were inhibited by exosomes from H37Rv-infeced cells including genes involved in antigen presentation. Moreover, this set of genes partially overlapped with the IFN-γ-induced genes inhibited by H37Rv infection. CONCLUSIONS: Our study suggests that exosomes, as carriers of M.tb pathogen associated molecular patterns (PAMPs), may provide a mechanism by which M.tb may exert its suppression of a host immune response beyond the infected cell. Public Library of Science 2011-04-14 /pmc/articles/PMC3077381/ /pubmed/21533172 http://dx.doi.org/10.1371/journal.pone.0018564 Text en Singh et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Singh, Prachi P.
LeMaire, Christopher
Tan, John C.
Zeng, Erliang
Schorey, Jeffery S.
Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title_full Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title_fullStr Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title_full_unstemmed Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title_short Exosomes Released from M.tuberculosis Infected Cells Can Suppress IFN-γ Mediated Activation of Naïve Macrophages
title_sort exosomes released from m.tuberculosis infected cells can suppress ifn-γ mediated activation of naïve macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077381/
https://www.ncbi.nlm.nih.gov/pubmed/21533172
http://dx.doi.org/10.1371/journal.pone.0018564
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