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PLoS Pathog
. 2020 Oct 26;16(10):e1008957.
doi: 10.1371/journal.ppat.1008957. Online ahead of print.
Dynamic metabolic reprogramming in dendritic cells: An early response to influenza infection that is essential for effector function
Svetlana Rezinciuc 1 , Lavanya Bezavada 1 , Azadeh Bahadoran 1 , Susu Duan 2 , Ruoning Wang 3 , Daniel Lopez-Ferrer 4 , David Finkelstein 5 , Maureen A McGargill 2 , Douglas R Green 2 , Ljiljana Pasa-Tolic 6 , Heather S Smallwood 1
Affiliations
- PMID: 33104753
- 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.