Glucose Metabolism and Innate Immune Responses in Influenza Virus Infection: Mechanistic Insights and Clinical Perspectives

Abstract

This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

Keywords: glucose metabolism; host-pathogen interactions; immune-metabolism; influenza; kinases; therapeutic targets.

Figure 1

Kinases as possible targets during influenza viral infection. Metabolic pathways in immune cells are modulated either through interactions with metabolic signals from the affected organs such as diverse conditions of nutrients and oxygen availability or co-effectors in their macro- and micro-environment, e.g., infection, infection products or chemicals. The need for energy for such cellular functions is essential, with glucose metabolism being the major carbon fuel source through two distinct pathways: glycolysis as a first path producing pyruvate and ATP and the tricarboxylic acid cycle as an immediate following path. Essential kinases of interest include rate-limiting enzymes such as hexokinase (HK), phosphofructokinases 1 (PFK1), pyruvate kinase (PK) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs).

Figure 2

The concept of trained immunity/immune reprogramming. Changes in innate immune cells can be achieved by epigenetic manipulation rather than permanent genetic modification. The production of dual innate adaptive vaccine products proposes a protective value for epigenetic changes and proposes a therapeutic potential when considering the associated kinases responding to the alterations in cellular energy.

Figure 3

Human cell responses to influenza viral infection. Pathogens are detected through the recognition of specific molecular structures or surface receptors that are absent from uninfected cells, termed pathogen-associated molecular patterns (PAMPs). Two types of pattern recognition receptors (PRRs), which are toll-like receptors (TLRs) and retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), can signal infection and then activate immune cells to produce specific markers. Each PRR depends on the cell type affected and the nature of the pathogen. Viruses attack both immune and somatic cells. When they attack somatic cells (A), mainly type I interferons are produced by infected cells, which act on both innate and adaptive immune cells to introduce these infected cells to innate immune monocytes and macrophages and present them to naive B cells, which then produce virus-specific antibodies. On the other hand, when the virus attacks immune cells (B), specific inflammatory cytokines are released. These include TNF-α as well as growth factors, which may lead to epithelial hyperplasia or plaque formation. Multiplication of viruses, however, in immune cells is controversial. TGFβ: transforming growth factor beta; PDGF: platelet-derived growth factor; TNFα: tumor necrosis factor alpha; INFγ: interferon gamma.

Figure 4

Cytokine–metabolism interactions during influenza virus infection of immune cells: Three inflammatory cytokines are highlighted in this work. (1) Type I IFN signals influenza infection, resulting in increased glycolysis and disruption of the TCA cycle. This mechanism involves stimulation of phosphatidylinositol-3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR)-dependent glucose uptake and disruption of TCA flux; (2) TNF-α induces ROS and nitric oxide production, stabilizing HIF-1α, that translocates to the nucleus, inducing the expression of glycolysis-activating genes, resulting in predominant lactate accumulation; (3)TGF-β1 is associated with increased lactate levels and PFK activity, establishing itself as a Smad-specific metabolic marker during influenza infection; (4) Among the metabolic enzymes that modulate glycolysis is PFK2 (PFK2/FBPase2), a family of bifunctional enzymes that control the levels of fructose-2,6-bisphosphate. PFK2 allosterically modulates the rate-limiting glycolytic enzyme PFK-1. Accordingly, a correlation might be expected between PFK1 and PFK2 expression levels and the grade of infection; (5) DCs can respond to influenza through a distinct metabolic phenotype, different from that induced by Toll-like receptor signaling, mediated by the transcription factor c-Myc. This metabolic reprogramming may impair DC functions related to T cell priming and optimal motility, thereby reducing DC migration and diminishing the capacity of the T cell response to infection. IFN: interferon; TNFα: tumor necrosis factor alpha; mTOR: mechanistic target of rapamycin; ROS: reactive oxygen species; HIF-1α: hypoxia-inducible factor 1 alpha; TGF β1: transforming growth factor β1; PFK: Phosphofructokinase; DCs: dendritic cells.