bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2025–04–06
six papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
  2. Foot-and-mouth disease virus activates glycolysis and hijacks HK2 to inhibit innate immunity and promote viral replication.
  3. Effects of the fatty acid synthase inhibitors triclosan and lapatinib on dengue virus and Zika virus infection.
  4. Integration of Transcriptomics and Metabolomics Reveals Metabolism Dysregulation in HIV-1-Infected Macrophages.
  5. Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in a hamster model of COVID-19.
  6. Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.
  1. Int Immunopharmacol. 2025 Mar 28. pii: S1567-5769(25)00541-7. [Epub ahead of print]154 114551
    Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
    Saurabh Losarwar, Bhaskaranand Pancholi, Raja Babu, Debapriya Garabadu.
      Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.
    Keywords:  Flavivirus; Innate immunity; Mitochondria; Mitochondrial antiviral signaling protein (MAVS); Mitochondrial dynamics (MD); RIG-I-like receptors (RLRs)
    DOI:  https://doi.org/10.1016/j.intimp.2025.114551
  2. Vet Res. 2025 Apr 01. 56(1): 71
    Foot-and-mouth disease virus activates glycolysis and hijacks HK2 to inhibit innate immunity and promote viral replication.
    Wenxian Chen, Xinyan Wang, Xiaowen Li, Weijun Wang, Yaoyao Huang, Yuwei Qin, Pengfei Liu, Keke Wu, Bingke Li, Yintao He, Sen Zeng, Lin Yi, Lianxiang Wang, Mingqiu Zhao, Hongxing Ding, Shuangqi Fan, Zhaoyao Li, Jinding Chen.
      Foot-and-mouth disease (FMD) severely restricts the healthy development of global animal husbandry, and the unclear pathogenic mechanism of FMD virus (FMDV) leads to difficulty in preventing and purifying FMD. Glycolytic remodelling is considered one of the hallmarks of viral infection, providing energy and precursors for viral assembly and replication. In this work, the interaction and mechanism between FMDV and glycolysis were explored from the perspective of immune metabolism. We found that FMDV infection increased the extracellular acidification rate, lactic acid accumulation, and HK2 level. In addition, during FMDV infection, HK2 enhances glycolytic activity and mediates autophagic degradation of IRF3/7 to antagonize the innate immune response, thereby promoting viral replication. Our findings provide evidence that FMDV is closely correlated with host metabolism, increasing the understanding that glycolysis and HK2 facilitate virus infection, and provide new ideas for further elucidating the pathogenic mechanism of FMDV.
    Keywords:  Foot-and-mouth disease virus; glycolysis; hexokinase 2; interferon regulatory factor; replication
    DOI:  https://doi.org/10.1186/s13567-025-01497-w
  3. Sci Rep. 2025 Mar 28. 15(1): 10731
    Effects of the fatty acid synthase inhibitors triclosan and lapatinib on dengue virus and Zika virus infection.
    Suthatta Sornprasert, Janejira Jaratsittisin, Chanida Chumchanchira, Duncan R Smith.
      Fatty acid synthase (FASN) has been shown to be critical in the replication of several viruses of the genus Orthoflavivirus. In this study the role two inhibitors of FASN that work through different mechanisms were investigated in dengue virus (DENV) and Zika virus (ZIKV) infections. Triclosan is a FASN inhibitor that targets the enol reductase domain of FASN, while lapatinib exerts an effect on FASN through acting on HER2, an upstream regulator of FASN. After determining cytotoxicity, a comprehensive analysis of the effect of these drugs in DENV 2 and ZIKV infection was undertaken. The results showed that triclosan had moderate antiviral activity against both DENV 2 (EC50 = 10.21 µM; Selective index (SI) = 3.99) and ZIKV ( EC50 = 22.84 µM; SI = 5.49). Lapatinib had reasonable activity against DENV 2 (EC50 = 4.9 µM; SI = 26.09), but computer modeling suggested that lapatinib had the potential to be a directly acting antiviral by binding to NS5. The result of that analysis suggested that lapatinib was a better fit with ZIKV NS5 than DENV NS5, and this was confirmed as the EC50 for lapatinib towards ZIKV was was 2 µM and the calculated SI was 37.92. The results of triclosan are consistent with other studies that use inhibitors that target other domains of FASN, suggesting that simply targeting the enzymatic activity of FASN is insufficient for therapeutic drug development, but that lapatinib, or similar molecules may have real therapeutic potential.
    DOI:  https://doi.org/10.1038/s41598-025-95346-7
  4. Curr Microbiol. 2025 Apr 04. 82(5): 232
    Integration of Transcriptomics and Metabolomics Reveals Metabolism Dysregulation in HIV-1-Infected Macrophages.
    Zongxiang Yuan, Chuye Mo, Yiwen Kang, Junhan Zhang, Fengyi Wang, Wudi Wei, Fang Qin, Shihui Huang, Junjun Jiang, Hao Liang, Li Ye.
      HIV-1 infection leads to metabolic changes in macrophages, yet a comprehensive understanding of its pathogenesis remains limited. To address this, we integrated transcriptomic and metabolomic analyses to uncover intracellular metabolic alterations in HIV-1-infected macrophages. We identified differentially expressed genes (DEGs) using RNA-sequencing, while metabolomic profiling was performed with UHPLC-QE-MS. The integration of transcriptomics and metabolomics was achieved through "Joint Pathway Analysis," and reverse transcription-quantitative PCR (RT-qPCR) was used to validate the identified pathways. Our transcriptomic analysis revealed a total of 890 DEGs, comprising 424 downregulated and 466 upregulated genes in macrophages infected with HIV-1. KEGG enrichment analysis highlighted the biosynthesis of amino acids and glycine, serine, and threonine metabolism as significantly enriched (P < 0.05). RT-qPCR results confirmed the expression of key genes, including PHGDH, PSAT1, PSPH, CBS, CTH, and AOC2, associated with these pathways. From the metabolomic analysis, we identified 60 differential metabolites, with glycerophospholipids representing the majority (51.67%). The integrated analysis revealed significant changes in glycine, serine, and threonine metabolism, glycerophospholipid metabolism, and linoleic acid metabolism in HIV-1-infected macrophages. This study offers an extensive overview of metabolic alterations in HIV-1-infected macrophages, which may enhance our understanding of the pathogenesis and highlight potential therapeutic targets.
    DOI:  https://doi.org/10.1007/s00284-025-04204-2
  5. Gut Microbes. 2025 Dec;17(1): 2486511
    Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in a hamster model of COVID-19.
    Patrícia Brito Rodrigues, Vinícius de Rezende Rodovalho, Valentin Sencio, Nicolas Benech, Marybeth Creskey, Fabiola Silva Angulo, Lou Delval, Cyril Robil, Philippe Gosset, Arnaud Machelart, Joel Haas, Amandine Descat, Jean François Goosens, Delphine Beury, Florence Maurier, David Hot, Isabelle Wolowczuk, Harry Sokol, Xu Zhang, Marco Aurélio Ramirez Vinolo, François Trottein.
      Aging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium, Oscillospiraceae, Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes.
    Keywords:  SARS-CoV-2; Viral pneumonia; aging; disease markers; gut microbiota; metabolomics; metagenomics
    DOI:  https://doi.org/10.1080/19490976.2025.2486511
  6. EBioMedicine. 2025 Mar 29. pii: S2352-3964(25)00116-1. [Epub ahead of print]114 105672
    Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.
    Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Olivier Lambotte, Dominique Costagliola, Mathieu F Chevalier, Laurence Weiss, Asier Sáez-Cirión.
       BACKGROUND: Virus-specific CD8+ T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8+ T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8+ T cells from people on antiretroviral treatment.
    METHODS: We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8+ T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8+ T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons.
    FINDINGS: Total and HIV-specific CD8+ T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ+ TNF-α+ cells. The superior CD8+ T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8+ T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment.
    INTERPRETATION: CD8+ T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections.
    FUNDING: The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).
    Keywords:  CD8(+) T cells; HIV control; HIV remission; HIV-1; Statins; T cell reprogramming
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105672
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