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Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections

Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, d...

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Autores principales: Lane, Sidney, White, Tristan L. A., Walsh, Erin E., Cattley, Richard T., Cumberland, Rachel, Hawse, William F., Delgoffe, Greg M., Badylak, Stephen F., Bomberger, Jennifer M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653878/
https://www.ncbi.nlm.nih.gov/pubmed/37772820
http://dx.doi.org/10.1128/mbio.00863-23
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author Lane, Sidney
White, Tristan L. A.
Walsh, Erin E.
Cattley, Richard T.
Cumberland, Rachel
Hawse, William F.
Delgoffe, Greg M.
Badylak, Stephen F.
Bomberger, Jennifer M.
author_facet Lane, Sidney
White, Tristan L. A.
Walsh, Erin E.
Cattley, Richard T.
Cumberland, Rachel
Hawse, William F.
Delgoffe, Greg M.
Badylak, Stephen F.
Bomberger, Jennifer M.
author_sort Lane, Sidney
collection PubMed
description Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, driven by miscommunication between cells responding to viruses and cells responding to bacteria. Previous studies have shown that antiviral signaling can influence EV cargo and promote antiviral defense in the recipient cell; however, how antiviral EVs may influence host defense against coinfecting microorganisms, specifically bacteria, is not known. Herein, we demonstrated that EVs released from the respiratory epithelium during antiviral signaling alter macrophage inflammatory signaling, induce anti-inflammatory metabolic reprogramming, and impair antibacterial activity against Staphylococcus aureus, a common coinfecting bacterial pathogen. Further proteomic analysis revealed that antiviral EVs are preferentially loaded with pyruvate kinase M2 (PKM2), a metabolic enzyme with immunomodulatory effects, and treatment with antiviral EVs leads to increased PKM2 in macrophages. Moreover, we showed that antiviral EV-treated macrophages displayed enhanced oxidative phosphorylation, a metabolic profile consistent with impaired S. aureus clearance, and that this metabolic state is phenocopied in macrophages treated with a PKM2 activator. Taken together, our findings identify EVs as a component of the epithelial antiviral response that contributes to impaired bacterial clearance through epithelial-macrophage crosstalk and suggest a role for EVs in driving disease progression during respiratory coinfection. IMPORTANCE: Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections.
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spelling pubmed-106538782023-09-29 Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections Lane, Sidney White, Tristan L. A. Walsh, Erin E. Cattley, Richard T. Cumberland, Rachel Hawse, William F. Delgoffe, Greg M. Badylak, Stephen F. Bomberger, Jennifer M. mBio Research Article Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, driven by miscommunication between cells responding to viruses and cells responding to bacteria. Previous studies have shown that antiviral signaling can influence EV cargo and promote antiviral defense in the recipient cell; however, how antiviral EVs may influence host defense against coinfecting microorganisms, specifically bacteria, is not known. Herein, we demonstrated that EVs released from the respiratory epithelium during antiviral signaling alter macrophage inflammatory signaling, induce anti-inflammatory metabolic reprogramming, and impair antibacterial activity against Staphylococcus aureus, a common coinfecting bacterial pathogen. Further proteomic analysis revealed that antiviral EVs are preferentially loaded with pyruvate kinase M2 (PKM2), a metabolic enzyme with immunomodulatory effects, and treatment with antiviral EVs leads to increased PKM2 in macrophages. Moreover, we showed that antiviral EV-treated macrophages displayed enhanced oxidative phosphorylation, a metabolic profile consistent with impaired S. aureus clearance, and that this metabolic state is phenocopied in macrophages treated with a PKM2 activator. Taken together, our findings identify EVs as a component of the epithelial antiviral response that contributes to impaired bacterial clearance through epithelial-macrophage crosstalk and suggest a role for EVs in driving disease progression during respiratory coinfection. IMPORTANCE: Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections. American Society for Microbiology 2023-09-29 /pmc/articles/PMC10653878/ /pubmed/37772820 http://dx.doi.org/10.1128/mbio.00863-23 Text en Copyright © 2023 Lane et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Lane, Sidney
White, Tristan L. A.
Walsh, Erin E.
Cattley, Richard T.
Cumberland, Rachel
Hawse, William F.
Delgoffe, Greg M.
Badylak, Stephen F.
Bomberger, Jennifer M.
Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title_full Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title_fullStr Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title_full_unstemmed Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title_short Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
title_sort antiviral epithelial-macrophage crosstalk permits secondary bacterial infections
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653878/
https://www.ncbi.nlm.nih.gov/pubmed/37772820
http://dx.doi.org/10.1128/mbio.00863-23
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