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

Abstract

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 SIRT1mediated regulation of metabolic processes.

Melatonin: Roles in influenza, Covid‐19, and other viral infections

“…37 Alterations in the levels and effects of cytosolic, nuclear, and mitochondrial sirtuins are also evident in a number of viral infections, including within dendritic cells, which have an important role in regulating the patterned immune response. 38 Generally, the sirtuins seem to be evolutionary conserved antiviral agents. 39 Like the circadian rhythm, viruses may act to disengage sirtuins from their regular physiological processes.…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…Acetyl-CoA carboxylase (ACC) leads to the irreversible carboxylation of acetyl-CoA, with AhR activation increasing ACC via Synphilin-1 degradation [ 78 ]. The suppression of sirtuin-1 in dendritic cells also increases ACC levels and decreases acetyl-CoA, with consequent alterations in mitochondrial metabolism that lead to dendritic cells inducing deficient anti-viral responses [ 79 ]. ACC blockade in this study led to dendritic cell metabolic reprogramming that ameliorated mitochondrial dysfunction and restored a more appropriate anti-viral response [ 79 ].…”

“…The suppression of sirtuin-1 in dendritic cells also increases ACC levels and decreases acetyl-CoA, with consequent alterations in mitochondrial metabolism that lead to dendritic cells inducing deficient anti-viral responses [ 79 ]. ACC blockade in this study led to dendritic cell metabolic reprogramming that ameliorated mitochondrial dysfunction and restored a more appropriate anti-viral response [ 79 ]. Such data highlights the important role that acetyl-CoA and its regulation by ACC have in determining and fine-tuning mitochondrial function [ 80 ], and the impact that alterations in mitochondrial function have on the immune regulatory responses of dendritic cells.…”

“…Preclinical data show the raised miR-155 levels in immune cells to accelerate ageing and decrease longevity via an increase in aerobic glycolysis and associated induction of pro-inflammatory processes [ 89 ]. The miR-155 inhibition of sirtuin-1 may be important to ageing via ACC upregulation and acetyl-CoA suppression [ 79 ], suggesting that miR-155 will associate with lower N-ASph, melatonin and acetylated-COX2. Melatonin increases sirtuins and decreases miR-155 levels [ 90 , 91 ], highlighting the importance of suppressed melatonin, including pineal and immune-derived melatonin.…”

Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach

“…It was reported that loss of SIRT1 further induced mRNA expression of IL-17 in an animal model of RSV infection [ 128 ]. According to their considerations, SIRT1-deficient bone marrow dendritic cells elevated Acetyl CoA carboxylase 1 (ACC1), which is associated with fatty acid synthesis, resulting in the activation of an abnormal metabolic process, which in turn preceded an excessive virus-induced immune response [ 128 ]. In other words, SIRT1 may regulate the Th17 immune response from virus-infected dendritic cells by regulating their metabolic pathways [ 128 ].…”