bims-mevinf 2025-11-30 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–11–30
ten papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

Remodelled cholesteryl ester enriched lipid droplets fuel flavivirus morphogenesis.
HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
WSSV-induced reversal of the malate-aspartate shuttle facilitates viral replication in shrimp hemocytes.
Metabolomic and clinical feature analyses of plasma from influenza A patients.
Integrated multiomics reveals host-virus coadaptation in persistent foot-and-mouth disease virus infection.
Thapsigargin suppresses porcine hemagglutinating encephalomyelitis virus replication by disrupting host energy metabolism.
Arginine Metabolism Supports De Novo Pyrimidine Biosynthesis to Block DNA Damage and Maintain Epstein-Barr Virus Latency.
Effect of Hepatitis C Virus Genotype, Cirrhosis, and Viral Cure on Serum Phosphatidylinositol Species Profiles.
Enhanced glycolysis and nicotinamide metabolism in HPV-positive head and neck cancer.
HBV induces liver fibrosis through the generation of reactive oxygen species in a pyruvate-dependent manner.

bioRxiv. 2025 Sep 30. pii: 2025.06.07.658178. [Epub ahead of print]

Remodelled cholesteryl ester enriched lipid droplets fuel flavivirus morphogenesis.

Adrianna Banducci-Karp, Sophie Brixton, Pranav N M Shah, Ming-Yuan Li, Georgina Fisher, Joey Riepsaame, Raman Dhaliwal, Katie L Holden, Edward Drydale, James Bancroft, Charlotte E Melia, Gathsaurie Neelika Malavige, Sumana Sanyal.

Flaviviruses such as dengue and Zika viruses extensively remodel host cell membranes to create specialised replication organelles, but the role of lipid metabolism to generate them remain poorly understood. Through systematic screens of fatty acyl transferase enzymes (MBOAT and zDHHC families) and complementary approaches including CRISPR/Cas9 gene deletions, pharmacological inhibition, proteomics, and photo-crosslinkable cholesterol analogues, we identified cholesteryl ester-enriched lipid droplets (CE-LDs) as critical host components required for flavivirus infection. CE-LD formation is mediated by Sterol O-acyltransferases 1 and 2 (SOAT1/SOAT2), whose activities were upregulated early during infection, coinciding with increased CE-LD formation and transition to liquid crystalline phases. Genetic deletion or pharmacological inhibition of either enzyme resulted in a dramatic ~100-fold reduction in viral production. Mechanistically, CE-LDs display distinct proteomic signatures, enriched in fatty acid remodelling enzymes, GTPases, and lipid transport proteins. Photo-crosslinking experiments demonstrated direct interactions between LD-derived cholesterol and viral prM, capsid and NS1. Disrupting CE-LD formation via SOAT1/2-deficiency resulted in defective, viral RNA-free replication organelles and complete absence of immature virions. Supporting the physiological and clinical relevance of viral LD exploitation, analysis in iPSC-derived macrophages mirrored findings in Huh7 cells, and dengue patients from a Sri Lankan cohort revealed that central obesity significantly increased the risk of severe dengue haemorrhagic fever. This study establishes CE-LDs as essential host metabolic hubs that enable flavivirus morphogenesis and identifies host LD metabolism as a promising therapeutic target for combating flavivirus infections.

DOI: https://doi.org/10.1101/2025.0.607.658178
bioRxiv. 2025 Oct 31. pii: 2025.10.31.685607. [Epub ahead of print]

HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.

Lucas A Simpson, Diana M Dunn, Wyatt Fales, Zachary J Moore, Jessica H Ciesla, Nicole Waild, Matthew H Raymonda, Isaac S Harris, Joshua Munger.

Human cytomegalovirus (HCMV) is a leading cause of congenital infection and morbidity in immunosuppressed populations. Like all viruses, HCMV is an obligate intracellular parasite that extensively remodels host cellular metabolism to support its replication, yet the precise underlying mechanisms and metabolic vulnerabilities remain poorly understood. Using a novel metabolism-focused screening platform, we identified EGLN prolyl hydroxylase activity as critical for HCMV infection. Our studies revealed that HCMV infection depends on EGLN1, which accumulated in mitochondria during infection. Inhibition of EGLN1 expression blocked HCMV-mediated mitochondrial activation, which in turn prevented the production of the dNTP precursors necessary for dNTP pool expansion and viral DNA replication. Further, pharmacological EGLN inhibition attenuated viral infection in a humanized mouse model. Collectively, these data establish EGLN1 as a critical determinant of mitochondrial metabolic remodeling and virally-induced dNTP generation during HCMV infection, highlighting EGLN1 as a promising novel antiviral therapeutic target.

DOI: https://doi.org/10.1101/2025.10.31.685607
Cell Commun Signal. 2025 Nov 26. 23(1): 507

WSSV-induced reversal of the malate-aspartate shuttle facilitates viral replication in shrimp hemocytes.

Fang-Jyun Guo, Kuan-Lun Huang, Cong-Yan Chen, Shu-Wen Cheng, Yen Siong Ng, Han-Ching Wang.

   BACKGROUND: White spot syndrome virus (WSSV), one of the most devastating pathogens in global shrimp aquaculture, has been shown to hijack and reprogram host metabolic pathways to support its replication. Among the various host metabolic circuits, the malate-aspartate shuttle (MAS) is a key redox-balancing mechanism that facilitates the translocation of cytosolic NADH into mitochondria, thereby sustaining glycolysis and mitochondrial function. To date, however, the involvement of MAS in WSSV pathogenesis has not been documented.
METHODS: In this study, we investigated the role of the MAS pathway in WSSV replication. We first assessed the mRNA level changes of MAS-related genes in WSSV infected shrimp. dsRNA-mediated gene silencing was also employed to examine its impact on the virus replication. To determine the direction of MAS during WSSV infection, we first silenced the MAS-related genes (e.g., GOT1 or GOT2), and subsequently replenished the corresponding metabolite to assess whether it could rescue the virus replication.
RESULTS: At the viral genome replication stage of WSSV infection (12 hpi), significant upregulation of key MAS-related genes, including LvGOT1, LvGOT2, LvMDH1, LvAGC, and LvOGC, was observed in hemocytes of infected shrimp. Functional knockdown of these genes by in vivo dsRNA-mediated gene silencing significantly reduced WSSV gene expression and viral genome copy number, indicating that MAS activity is required for efficient WSSV replication. Furthermore, metabolite rescue experiments revealed a potential reversal of the MAS flux during the infection: supplementation with aspartate or α-ketoglutarate restored viral replication in LvGOT1-silenced shrimp, while oxaloacetate supplementation reversed the lowered replication caused by LvMDH1 silencing.
CONCLUSION: This study demonstrates that WSSV activates the host MAS pathway to facilitate its replication and highlights the dynamic reprogramming of redox-associated mitochondrial metabolism in response to WSSV infection. The WSSV-induced reversed MAS might supply specific metabolites such as aspartate needed for virus replication or to prevent the TCA shut down.

Keywords:   Litopenaeus vannamei ; Aspartate-glutamate carrier; Glutamate-oxaloacetate transaminase; Malate dehydrogenase; Malate-aspartate shuttle; Oxoglutarate carrier; White spot syndrome virus

DOI:  https://doi.org/10.1186/s12964-025-02506-3
Sci Rep. 2025 Nov 28. 15(1): 42616

Metabolomic and clinical feature analyses of plasma from influenza A patients.

Yaping Li, Ting Li, Min Liu, XinYu Wang, Song Zhai, Ruihong Qin, Chenrui Liu, Yuanyi Chen, Meng Zhang, Xiaoli Jia.

  Plasma metabolomics offers valuable insights for identifying viral infection biomarkers with applications in early diagnosis, outcome prediction, and treatment monitoring. This study aimed to investigate metabolomic alterations in influenza A patients and identify potential biomarkers for disease severity. From March 2023 to March 2024, 339 influenza A patients were enrolled. After age‒sex matching, 54 patients and 20 healthy controls were selected for analysis. Untargeted metabolomic profiling of 74 plasma samples was conducted using ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry. Comparative analysis revealed 60 differentially expressed metabolites between H1N1 patients and healthy controls, with 41 significantly upregulated and 19 downregulated. Pathway enrichment analysis revealed prominent disruptions in glycerophospholipid metabolism, with several metabolites showing alterations across the severity spectrum. Amino acid metabolism, particularly propionate metabolism, glycine-serine-threonine metabolism, and branched-chain amino acid biosynthesis, was also notably disturbed. Critical exhibited marked disturbances in taurine-hypotaurine metabolism compared to milder. This study identified glycerophospholipid metabolism dysregulation as a potential biomarker for influenza severity stratification. The progressive alteration of taurine pathway metabolites in critical suggests their pivotal role in severe H1N1 pathogenesis, highlighting their dual potential as diagnostic biomarkers and therapeutic targets.

Keywords:  Glycerophospholipids; Influenza A (H1N1); Metabolic profiling; Severity biomarkers; Taurine metabolism

DOI:  https://doi.org/10.1038/s41598-025-26805-4
Cell Mol Life Sci. 2025 Nov 24.

Integrated multiomics reveals host-virus coadaptation in persistent foot-and-mouth disease virus infection.

Shuang Wang, Zhihui Zhang, Sumin Wei, Guoliang Huang, Shuanghui Yin, Suyu Mu, Hu Dong, Shiqi Sun, Huichen Guo.

  A comprehensive understanding of host-virus interactions during persistent foot-and-mouth disease virus (FMDV) infection is essential for elucidating the mechanisms that underpin disease causation by this highly contagious pathogen. This understanding necessitates the development of stable in vitro models. In this study, we established a model of persistent FMDV serotype O infection in Madin-Darby bovine kidney epithelial cells followed by integrated multiomics analyses. These analyses revealed that host cells adapt to persistent viral infection by reprogramming mitochondrial metabolism. This reprogramming is accompanied by alterations in mitochondrial structure and function, as well as the suppression of the apoptotic response in host cells. In particular, bystander cells, which are devoid of active viral replication, display enhanced proliferative capacity and possess a distinct microenvironmental signature that potentially increases viral susceptibility, facilitating sustained virus persistence within the cell population. Moreover, persistent viruses have evolved enhanced replicative fitness. Our findings elucidate the biological characteristics of FMDV-infected cell populations that persistently harbour the virus, reveal host-virus coadaptation, and highlight the critical role of bystander cells in sustaining persistent FMDV infection. These discoveries establish the foundation for further mechanistic studies of FMDV persistence maintenance.

Keywords:  Host adaptation; Mitochondrial damage; Systems biology; Viral fitness; Virus-eliminated cells

DOI:  https://doi.org/10.1007/s00018-025-05997-y
Virol Sin. 2025 Nov 21. pii: S1995-820X(25)00161-0. [Epub ahead of print]

Thapsigargin suppresses porcine hemagglutinating encephalomyelitis virus replication by disrupting host energy metabolism.

Qianhan Jia, Zi Li, Yanfang Yu, Zezhao Cao, Ruizhao Qiu, Jing Zhang, Wenqi He, Junchao Shi.

  Coronaviruses (CoVs) are a large family of human and animal pathogens that cause significant health and economic burdens worldwide. Thapsigargin (Tg) is a plant-derived sesquiterpene lactone with potent antiviral effects; however, the underlying mechanism remains unclear. Here, we show that Tg exhibited strong antiviral activity against the neurotropic swine CoV porcine hemagglutinating encephalomyelitis virus (PHEV) both in vivo and in vitro. Tg also exhibited inhibitory activity against other three swine coronaviruses in cell lines. Specifically, Tg treatment significantly inhibited the replication and transcription of genomic RNA in the viral life cycle but did not directly inactivate PHEV. Transcriptome analysis and glycolysis/mitochondrial stress testing confirmed that Tg alters intracellular metabolic flux, and suppresses glycolysis and oxidative phosphorylation (OXPHOS). Furthermore, metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection. Overall, our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms, suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses.

Keywords:  Metabolic reprogramming; Porcine hemagglutinating encephalomyelitis virus (PHEV); Swine coronavirus; Thapsigargin (Tg)

DOI:  https://doi.org/10.1016/j.virs.2025.11.006
bioRxiv. 2025 Oct 21. pii: 2025.10.21.683727. [Epub ahead of print]

Arginine Metabolism Supports De Novo Pyrimidine Biosynthesis to Block DNA Damage and Maintain Epstein-Barr Virus Latency.

Shaowen White, Yifei Liao, Eric M Burton, John M Asara, Benjamin E Gewurz.

  Incompletely understood mechanisms serve to maintain Epstein-Barr virus (EBV) latency in most B-cell states, in which viral oncogene(s) are expressed but lytic antigens are repressed. Shortly after EBV's discovery and even before it was named, early pioneers Werne and Gertrude Henle identified that restriction of extracellular arginine de-represses EBV lytic antigens within Burkitt lymphoma tumor cells. However, for nearly 60 years, it has remained unknown how arginine metabolism supports EBV latency. To gain insights, we performed an amino acid restriction screen in Burkitt cell lines. This confirmed that arginine restriction was sufficient to trigger EBV reactivation in Burkitt B-cells and gastric carcinoma models. Arginine restriction strongly impaired de novo pyrimidine biosynthesis, and CRISPR or chemical genetic blockade of pyrimidine biosynthesis enzymes induced EBV immediate early and early lytic gene expression. However, arginine restriction blocked EBV lytic DNA replication and consequently also late gene expression, suggesting an abortive lytic cycle. Arginine restriction triggered DNA damage, which was an important driver of arginine restriction-driven EBV reactivation. Arginine restriction and DNA hypomethylation synergistically increased EBV reactivation. Together, our results highlight arginine and pyrimidine metabolism as potential targets for EBV lytic antigen induction therapy in B and epithelial cell contexts.

Keywords:  DNA damage; de novo pyrimidine synthesis; double-stranded DNA virus; epigenetic; lytic cycle; metabolism; nucleotide biosynthesis; nucleotide metabolism; reactivation; viral latency

DOI:  https://doi.org/10.1101/2025.10.21.683727
Biomedicines. 2025 Nov 06. pii: 2720. [Epub ahead of print]13(11):

Effect of Hepatitis C Virus Genotype, Cirrhosis, and Viral Cure on Serum Phosphatidylinositol Species Profiles.

Kilian Weigand, Georg Peschel, Marcus Höring, Sabrina Krautbauer, Gerhard Liebisch, Martina Müller, Christa Buechler.

  Background/Objectives: Phosphatidylinositol (PI) species are bioactive lipids implicated in liver fibrogenesis. Hepatitis C virus (HCV) relies on host lipid metabolism for infection. The relationship between serum PI profiles, chronic HCV, and liver injury remains incompletely defined. Methods: Fourteen PI species were quantified by direct flow injection-tandem mass spectrometry (FIA-MS/MS; triple quadrupole) in serum from 178 patients with chronic HCV at three time points: before treatment and at weeks 4 and 12 after starting direct-acting antiviral (DAA) therapy. Results: At baseline, PI 34:1, 36:1, and 36:3 were higher in patients with ultrasound-diagnosed cirrhosis than in those without, whereas PI 38:4, 40:5, and 40:6 were lower. In non-cirrhotic patients, PI 36:3, 36:4, 38:3, 38:4, and 38:5 increased, while PI 40:5 and 40:6 declined at weeks 4 and 12 after therapy start. In cirrhosis, viral cure was not associated with changes in PI species. By the end of therapy, cirrhotic patients showed higher PI 36:3 and lower PI 38:4 than non-cirrhotic patients. Genotype 3a was associated with lower PI 38:3, 38:4, and 38:5; the reduction in PI 38:4 persisted to the end of therapy. Across time points, most PI species did not correlate with routine markers of liver injury or inflammation. Conclusions: HCV cure remodels the serum PI profile in non-cirrhotic patients. These findings suggest that altered PI profiles are primarily linked to HCV infection, supporting a role for PI lipids in viral propagation.

Keywords:  genotype; hepatitis C; lipid species; liver cirrhosis

DOI:  https://doi.org/10.3390/biomedicines13112720
Sci Rep. 2025 Nov 28. 15(1): 42714

Enhanced glycolysis and nicotinamide metabolism in HPV-positive head and neck cancer.

Katie A Shen, Jae-Jin Lee, Shu-Yun Cheng, Ella P Jackert, Liyang Tang, Daniel Kwon, Niels Kokot, Uttam Sinha, Yang Chai, Hyungjin Eoh, Albert Y Han.

  Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally, with increasing prevalence driven largely by human papillomavirus (HPV) infection. Current standard therapies frequently leave patients with severe, long-term functional impairments, significantly reducing quality of life. Although HPV-positive HNSCC has improved prognosis and better treatment responses compared to HPV-negative disease, the underlying metabolic distinctions remain poorly defined. Using comprehensive metabolomic profiling via ultra-performance liquid chromatography-mass spectrometry in well-established HPV-positive (SCC47, SCC104) and HPV-negative (Detroit562, SCC9) HNSCC cell lines, we demonstrate for the first time through comprehensive metabolomic analysis that HPV-positive HNSCC uniquely enhances metabolic pathways advantageous for rapid cell proliferation, including glycolysis and nicotinamide metabolism. Conversely, HPV-negative HNSCC primarily relies on downstream components of the tricarboxylic acid cycle for energy production. Identifying these differential metabolic has important implications for precision-oncology in the development of targeted therapeutics for HPV-positive HNSCC patients.

Keywords:  Head and neck cancer; Human papillomavirus; Metabolism; Metabolomics; Warburg effect

DOI:  https://doi.org/10.1038/s41598-025-26690-x
Hepatology. 2025 Oct 30.

HBV induces liver fibrosis through the generation of reactive oxygen species in a pyruvate-dependent manner.

Xiaoqiong Duan, Shasha Li, Qingyuan Li, Wenxian Wen, Olivia Mezzetti, Charlotte Warner, Min Xu, Andre J Jeyarajan, Yujia Li, Yaoqiang Shi, Ning Jiang, Wenting Li, Chunhui Yang, Youmin Yang, Jing Xu, Min Xu, He Xie, Shilin Li, Raymond T Chung, Xianding Wang, Limin Chen, Wenyu Lin.

   BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is a major etiology of liver cirrhosis. We previously found that pyruvate, a key intermediate in many metabolic pathways, increases HBV replication. However, the mechanism by which pyruvate mediates HBV-induced liver fibrosis is not well characterized. We hypothesize that HBV induces liver fibrosis through a pyruvate-peroxisome proliferator-activated receptor α (PPARα) - reactive oxygen species (ROS) pathway.
APPROACH AND RESULTS: We evaluated HBV-induced fibrogenesis in HepAD38, HBV-infected NTCP-HepG2, primary human hepatocytes (PHHs), and hepatic stellate cell lines (HSC, LX2) in mono- and co-culture models and in patient sera. We also evaluated the effects of PPARα agonist/antagonist and ROS inhibition on HBV-induced liver fibrosis in cell culture, HBV carrier mouse, HBV-Transgenic mouse (HBV-Tg), humanized liver mouse, and human precision-cut liver slice (PCLS) models. We found that HBV increased pyruvate levels and fibrosis-related gene expression in both HBV-infected hepatocytes and patient sera. Supernatants from HBV-infected cells (HBVsup) and pyruvate supplementation independently and additively increased expression of profibrotic genes (TGF-β1, TIMP-1, COL1A1, and α-SMA), activated ROS production, and inhibited PPARα expression. Notably, PPARα inhibition and siRNA knockdown increased ROS production and profibrogenic gene expression, while activation of PPARα blocked HBVsup- and pyruvate-induced ROS generation and fibrogenesis. ROS was confirmed to be downstream of PPARα-related fibrogenesis, as ROS inhibition abrogated HBVsup-, pyruvate supplementation-, or PPARα inhibition-induced liver fibrosis.
CONCLUSIONS: HBV infection induces pyruvate production and decreases PPARα expression, leading to increased ROS generation and liver fibrosis. Pyruvate and PPARα represent novel targets for antifibrotic therapeutic development in CHB.

Keywords:  Hepatitis B virus; PPARα; ROS generation; liver fibrogenesis; pyruvate

DOI:  https://doi.org/10.1097/HEP.0000000000001597