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Review
. 2025 May 16:16:1578202.
doi: 10.3389/fimmu.2025.1578202. eCollection 2025.

Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses

Mahmoud Darweesh  1   2 , Saeed Mohammadi  1 , Mina Rahmati  3 , Moosa Al-Hamadani  1 , Ahmed Al-Harrasi  4
Affiliations
Review

Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses

Mahmoud Darweesh et al. Front Immunol. .

Abstract

Metabolic reprogramming is an important player within the immune response to viral infections, allowing immune cells to fine-tune their energy production and biosynthetic requirements while it is actively working to restrict pathogen access to essential nutrients. Particularly, glucose metabolism, which appears to be one of the important regulators of immune function, affects immune cell activation, cytokine secretion, and pathogen restriction. This review explores the mechanisms of metabolic reprogramming during viral infections, with a specific emphasis on glucose metabolism. We discussed the key cytokines involved in orchestrating this metabolic process and the influence of pre-existing metabolic disorders on immune efficiency. Furthermore, we introduced emerging therapeutic strategies that target glucose metabolism to enhance antiviral immunity and improve disease outcomes. A deeper understanding of the interaction between metabolism and immunity could be promising for the development of novel immunometabolic targets against viral infections.

Keywords: cytokines; diabetes; glucose metabolism; immune activation; immunometabolism; pathogen clearance; viral infections.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Overview of metabolic reprogramming of glucose metabolism during viral infection. This figure illustrates how viral infection reprograms host glucose metabolism by modulating key metabolic regulators and pathways. Viral infection (red) triggers metabolic shifts by activating mTOR (orange) and HIF-1α (blue) while suppressing AMPK (green), leading to enhanced glycolysis, pentose phosphate pathway (PPP) activity, and reduced fatty acid oxidation (FAO). Increased glycolysis and PPP provide essential metabolic intermediates for viral replication and immune cell activation. Additionally, viral infection promotes inflammatory cytokine release (TNF, IL-6, IFN-β), further fueling metabolic shifts. Macrophage polarization is influenced by these metabolic changes, with M1 macrophages favoring glycolysis and M2 macrophages relying on FAO. T cell dysfunction arises due to metabolic stress and chronic mTOR activation.
Figure 2
Figure 2
Dual Role of Glucose in Immune Activation and Pathogen Restriction. This figure illustrates the contrasting roles of glucose metabolism in immune responses and viral restriction. The section (A) depicts how glucose uptake supports immune cell activation, proliferation, and cytokine production, enhancing antiviral defense. The section (B) demonstrates how glucose restriction, mediated by cytokines such as IFNγ and IL-1β, limits viral replication by depriving infected cells of essential nutrients.
Figure 3
Figure 3
Comparative analysis of glucose metabolism across different viral subtypes. Respiratory viruses (Influenza, RSV, SARS-CoV-2) enhance glycolysis in alveolar epithelial cells and immune cells, leading to cytokine storms and inflammation. Hepatotropic viruses (HBV, HCV) reprogram hepatocyte metabolism by increasing glycolysis and disrupting insulin signaling. Neurotropic viruses (HSV, Rabies, Zika) manipulate glucose metabolism in neurons and glial cells, contributing to neuroinflammation and viral persistence. Systemic viruses (DENV, CMV, HIV) alter metabolic pathways in immune and endothelial cells, driving systemic inflammation and immune exhaustion.
Figure 4
Figure 4
Roadmap for future research in immunometabolism and viral infections.
See this image and copyright information in PMC

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