Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), a NAD+ dependent deacetylase, has been associated with induction of autophagy, reprogramming cellular metabolism, and regulating immune mediators. In this study, we inv...

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Autores principales:	Srikanth Elesela, Susan B Morris, Samanthi Narayanan, Surinder Kumar, David B Lombard, Nicholas W Lukacs
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/23a18838d5664fb290b5aa945c0eccf1
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spelling	oai:doaj.org-article:23a18838d5664fb290b5aa945c0eccf12021-12-02T19:59:38ZSirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.1553-73661553-737410.1371/journal.ppat.1008319https://doaj.org/article/23a18838d5664fb290b5aa945c0eccf12020-02-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1008319https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), a NAD+ dependent deacetylase, has been associated with induction of autophagy, reprogramming cellular metabolism, and regulating immune mediators. In this study, we investigated the role of SIRT1 in bone marrow dendritic cell (BMDC) function during RSV infection. SIRT1 deficient (SIRT1 -/-) BMDC showed a defect in mitochondrial membrane potential (Δ⍦m) that worsens during RSV infection. This defect in Δ⍦m caused the generation of elevated levels of reactive oxygen species (ROS). Furthermore, the oxygen consumption rate (OCR) was reduced as assessed in Seahorse assays, coupled with lower levels of ATP in SIRT1-/- DC. These altered responses corresponded to altered innate cytokine responses in the SIRT1-/- DC in response to RSV infection. Reverse Phase Protein Array (RPPA) functional proteomics analyses of SIRT1-/- and WT BMDC during RSV infection identified a range of differentially regulated proteins involved in pathways that play a critical role in mitochondrial metabolism, autophagy, oxidative and ER stress, and DNA damage. We identified an essential enzyme, acetyl CoA carboxylase (ACC1), which plays a central role in fatty acid synthesis and had significantly increased expression in SIRT1-/- DC. Blockade of ACC1 resulted in metabolic reprogramming of BMDC that ameliorated mitochondrial dysfunction and reduced pathologic innate immune cytokines in DC. The altered DC responses attenuated Th2 and Th17 immunity allowing the appropriate generation of anti-viral Th1 responses both in vitro and in vivo during RSV infection thus reducing the enhanced pathogenic responses. Together, these studies identify pathways critical for appropriate DC function and innate immunity that depend on SIRT1-mediated regulation of metabolic processes.Srikanth EleselaSusan B MorrisSamanthi NarayananSurinder KumarDavid B LombardNicholas W LukacsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 16, Iss 2, p e1008319 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Srikanth Elesela Susan B Morris Samanthi Narayanan Surinder Kumar David B Lombard Nicholas W Lukacs Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
description	Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), a NAD+ dependent deacetylase, has been associated with induction of autophagy, reprogramming cellular metabolism, and regulating immune mediators. In this study, we investigated the role of SIRT1 in bone marrow dendritic cell (BMDC) function during RSV infection. SIRT1 deficient (SIRT1 -/-) BMDC showed a defect in mitochondrial membrane potential (Δ⍦m) that worsens during RSV infection. This defect in Δ⍦m caused the generation of elevated levels of reactive oxygen species (ROS). Furthermore, the oxygen consumption rate (OCR) was reduced as assessed in Seahorse assays, coupled with lower levels of ATP in SIRT1-/- DC. These altered responses corresponded to altered innate cytokine responses in the SIRT1-/- DC in response to RSV infection. Reverse Phase Protein Array (RPPA) functional proteomics analyses of SIRT1-/- and WT BMDC during RSV infection identified a range of differentially regulated proteins involved in pathways that play a critical role in mitochondrial metabolism, autophagy, oxidative and ER stress, and DNA damage. We identified an essential enzyme, acetyl CoA carboxylase (ACC1), which plays a central role in fatty acid synthesis and had significantly increased expression in SIRT1-/- DC. Blockade of ACC1 resulted in metabolic reprogramming of BMDC that ameliorated mitochondrial dysfunction and reduced pathologic innate immune cytokines in DC. The altered DC responses attenuated Th2 and Th17 immunity allowing the appropriate generation of anti-viral Th1 responses both in vitro and in vivo during RSV infection thus reducing the enhanced pathogenic responses. Together, these studies identify pathways critical for appropriate DC function and innate immunity that depend on SIRT1-mediated regulation of metabolic processes.
format	article
author	Srikanth Elesela Susan B Morris Samanthi Narayanan Surinder Kumar David B Lombard Nicholas W Lukacs
author_facet	Srikanth Elesela Susan B Morris Samanthi Narayanan Surinder Kumar David B Lombard Nicholas W Lukacs
author_sort	Srikanth Elesela
title	Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
title_short	Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
title_full	Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
title_fullStr	Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
title_full_unstemmed	Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
title_sort	sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/23a18838d5664fb290b5aa945c0eccf1
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Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.

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