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

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.

Dynamic Pneumococcal Genetic Adaptations Support Bacterial Growth and Inflammation during Coinfection with Influenza

“…Altered metabolic regulation has been observed during murine influenza virus infection (54)(55)(56)(57), in vitro influenza virus infection of primary human bronchotracheal epithelial (HBAE) cells (58,59), and in pediatric patients infected with influenza virus (58).…”

“…Glutamine is utilized at a high rate by immune cells and is needed for optimal function of macrophages and neutrophils(68)(69)(70)(71)(72)(73). Since pulmonary cells have increased dependence on glutamine during influenza virus infection(57,58), it is probable that competition for limited, enivonmentally available glutamine altered (putative cobalt transporter) was previously identified by microarray analysis as necessary for pneumococcal pathogenicity(42). Interestingly, bacteria lacking SPD2047 reach significantly higher lung titers in IAV-infected animals than in mock-infected animals (Fig4A-D), suggesting that cobalt metabolism may be modified by influenza virus infection.…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…Exposing cells to high glucose significantly increased viral infection, whereas viral replication was significantly reduced after using glycolytic inhibitors, and viral infection was restored after adding exogenous ATP ( Kohio and Adamson, 2013 ). Other studies have shown that cellular glycolytic flux is significantly increased during viral infection and is a major source of ATP ( Rezinciuc et al, 2020 ), as viral entry initiates glycolysis, and viral replication amplifies this metabolic change. Glycolysis provides the required metabolic fuel for virus replication, while inhibition of glycolysis reduces viral titers ( Smallwood et al, 2017 ).…”

“…Upregulation of c-Myc in four DNA tumor viruses, human adenovirus, human papillomavirus, EBV, and Kaposi’s associated sarcoma herpesvirus, affects cellular metabolism ( Prusinkiewicz and Mymryk, 2021 ). Glycolysis and c-Myc expression were increased in DC cells infected with IAV while inhibiting c-Myc activity blocked the increase of glycolysis induced by IAV ( Rezinciuc et al, 2020 ).…”

Reprogramming of Central Carbon Metabolism in Myeloid Cells upon Innate Immune Receptor Stimulation

“…MAVS signalosome drives IRF3 and NF-κB activation by TBK1 and IKKε, resulting in type I IFN and inflammatory cytokines production [49]. Influenza virus infection of bone-marrow-derived dendritic cells (BMDCs) increases glycolytic activity similarly to TLR stimulation but also increases basal respiration in contrast to TLR3, 4 and 8 stimulation [50]. The specific stimulation of RIG-I also results in enhanced glycolytic activity in human MoDCs, allowing type-I IFN synthesis [51].…”