Dynamic metabolic reprogramming in dendritic cells: An early response to influenza infection that is essential for effector function.

Svetlana Rezinciuc,Heather S Smallwood,Susu Duan,Ljiljana Pasa-Tolic,Ruoning Wang,Maureen A Mcgargill,Lavanya Bezavada,David Finkelstein,Daniel Lopez-Ferrer,Azadeh Bahadoran,Douglas R Green,Daniel R Perez

doi:10.1371/journal.ppat.1008957

Abstract

Infection with the influenza virus triggers an innate immune response that initiates the adaptive response to halt viral replication and spread. However, the metabolic response fueling the molecular mechanisms underlying changes in innate immune cell homeostasis remain undefined. Although influenza increases parasitized cell metabolism, it does not productively replicate in dendritic cells. To dissect these mechanisms, we compared the metabolism of dendritic cells to that of those infected with active and inactive influenza A virus and those treated with toll-like receptor agonists. Using quantitative mass spectrometry, pulse chase substrate utilization assays and metabolic flux measurements, we found global metabolic changes in dendritic cells 17 hours post infection, including significant changes in carbon commitment via glycolysis and glutaminolysis, as well as mitochondrial respiration. Influenza infection of dendritic cells led to a metabolic phenotype distinct from that induced by TLR agonists, with significant resilience in terms of metabolic plasticity. We identified c-Myc as one transcription factor modulating this response. Restriction of c-Myc activity or mitochondrial substrates significantly changed the immune functions of dendritic cells, such as reducing motility and T cell activation. Transcriptome analysis of inflammatory dendritic cells isolated following influenza infection showed similar metabolic reprogramming occurs in vivo. Thus, early in the infection process, dendritic cells respond with global metabolic restructuring, that is present in inflammatory lung dendritic cells after infection, and this is important for effector function. These findings suggest metabolic switching in dendritic cells plays a vital role in initiating the immune response to influenza infection.

Highlights

The influenza virus is associated with significant disease burden in the human population and is of high risk to children, the elderly, and those with certain medical conditions, such as pregnancy, obesity, or metabolic disease
We present data indicating the metabolic response of dendritic cells is increased yet flexible, distinct from what we previously showed for epithelial cells
The dendritic cells (DC) proteomes are publicly available in the Proteomics Identifications (PRIDE) repository (PXD013690)

Summary

Introduction

The influenza virus is associated with significant disease burden in the human population and is of high risk to children, the elderly, and those with certain medical conditions, such as pregnancy, obesity, or metabolic disease. Influenza is sensed intracellularly by TLR3, TLR7, or TLR8, and TLR9, sensing either viral envelope proteins or nucleic acids, respectively [6,7,8,9,10,11,12] These TLRs are expressed at variable levels in human and murine cells of the upper respiratory tract, such as epithelial cells, macrophages, and dendritic cells [13]. The stimulation of these intracellular receptors tailor the antiviral response via retinoic acid-inducible gene-I (RIG-I) and NOD-like receptors or lack thereof, creating a cell-specific response to influenza infection [13]. The metabolic response of dendritic cells to influenza infection remains undefined, as does its relationship to TLR stimulation and inactive virus

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