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 SIRT1-mediated regulation of metabolic processes.
Highlights
Human Respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus that belongs to the Paramyxoviridae family
These studies further demonstrate that regulation of dendritic cell metabolism is mediated by Sirtuin 1 (SIRT1), a critical cellular sensor that controls both cellular and mitochondrial protein activation that facilitates proper innate immune activation
The absence of SIRT1 in DC leads to inappropriate metabolic processes, including fatty acid synthesis through Acetyl Co A pathways, which enhances the pathogenic immune responses leading to inappropriately modified acquired immunity
Summary
Human Respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus that belongs to the Paramyxoviridae family. It is the leading cause of acute respiratory infection during early childhood and is associated with a significant morbidity and mortality among infants, the elderly, and patients with chronic respiratory diseases worldwide [1,2,3]. Elevated levels of the proinflammatory cytokines, IL-1, IL-6, and IL-17A, have been observed in respiratory aspirate samples from patients hospitalized with RSV infections [6,7,8]. The development of drugs to treat RSV infection is an unmet need
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