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

Author summary Dendritic cells are critical in mounting an effective immune response to influenza infection by initiating the immune response to influenza and activating the adaptive response to mediate viral clearance and manifest immune memory for protection against subsequent infections. We found dendritic cells undergo a profound metabolic shift after infection. They alter the concentration and location of hundreds of proteins, including c-Myc, facilitating a shift to a highly glycolytic phenotype that is also flexible in terms of fueling respiration. Nonetheless, we found limiting access to specific metabolic pathways or substrates diminished key immune functions. We previously described an immediate, fixed hypermetabolic state in infected respiratory epithelial cells. Here we present data indicating the metabolic response of dendritic cells is increased yet flexible, distinct from what we previously showed for epithelial cells. Additionally, we demonstrate dendritic cells tailor their metabolic response to the pathogen or TLR stimulus. This metabolic reprogramming occurs rapidly in vitro and is sustained in inflammatory dendritic cells in vivo for at least 9 days following influenza infection. These studies introduce the possibility of modulating the immune response to viral infection using customized metabolic therapy to enhance or diminish the function of specific cells. 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.