bims-mevinf 2025-11-16 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–11–16
twelve papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

Japanese encephalitis virus promotes its replication in neuronal cells by enhancing glycolysis via hypoxia-inducible factor-1α.
Synergetic contributions of Seneca Valley virus 3 C and 3D proteins to induction of ferroptosis for viral replication.
Pathogenic dengue virus TW2015 strain infection triggers anaerobic glycolysis and enhances mortality in diabetic mice.
Unraveling virus-host interactions: Current advances in viral lipidomics.
A novel antiviral strategy by disrupting the equilibrium of virus-host calcium homeostasis.
Grass Carp Catalase Inhibits Interferon Regulatory Factor-7 to Promote Grass Carp Reovirus Replication.
Ceramide synthase 4 interferes with replication of influenza virus but is downregulated by infection.
Calycosin inhibits porcine reproductive and respiratory syndrome virus replication and activates RIG-I/IRF3 signaling pathway.
Baicalin inhibits infectious bronchitis virus replication via MAVS-dependent interferon-β upregulation and mitochondrial function preservation.
Itaconate reduces viral endocytosis by targeting Cys128 of the adaptor-related protein complex 1 gamma 1 subunit in the host, providing a novel target for antiviral drug development.
Epstein-Barr virus-transformed B-cells from a Hypoxia model of the germinal center requires external unsaturated fatty acids.
Human-specific activation of the DUX4-SLC34A2 axis by herpesviruses suppresses antiviral innate immunity.

Virology. 2025 Nov 06. pii: S0042-6822(25)00350-2. [Epub ahead of print]614 110736

Japanese encephalitis virus promotes its replication in neuronal cells by enhancing glycolysis via hypoxia-inducible factor-1α.

Vijay Singh Bohara, Sachin Kumar.

  Japanese encephalitis virus (JEV), a causative agent of viral encephalitis, manipulates host metabolic pathways to support its replication in the host cells. Glycolysis is one of the crucial metabolic pathways regulated by most of the RNA viruses. In the current study, we investigated the regulation of glycolysis by JEV in Neuro-2a cells. JEV replication induces a time-dependent increase in glycolysis, demonstrated by decreased glucose and elevated lactic acid levels in the supernatant of infected cells. Furthermore, treatment with glycolytic inhibitors, such as 2-Deoxy-D-glucose and sodium oxamate, reduced virus replication. Moreover, supplementation with sodium pyruvate, an alternate energy source, and treatment with insulin promoted JEV replication, highlighting their positive role during metabolic stress in JEV-infected cells. JEV replication also enhanced the expression of several glycolytic enzymes. We identified hypoxia-inducible factor-1α (HIF-1α) as a critical regulator of glycolysis during JEV infection. JEV infection resulted in HIF-1α upregulation, indicating its role in replication kinetics. Cobalt chloride-induced stabilization of HIF-1α enhanced JEV replication, while its knockdown abrogated this effect in treated cells. Altogether, our results reveal that JEV modulates host glucose metabolism via HIF-1α to facilitate its replication and also highlight glycolytic inhibitors as potential antiviral against JEV.

Keywords:  2-Deoxy-D-glucose; Glycolysis; Hypoxia-inducible factor 1α; Japanese encephalitis virus; Sodium oxamate

DOI:  https://doi.org/10.1016/j.virol.2025.110736
Cell Mol Life Sci. 2025 Nov 14. 82(1): 406

Synergetic contributions of Seneca Valley virus 3 C and 3D proteins to induction of ferroptosis for viral replication.

Jiangwei Song, Jingjing Yang, Ruiyi Ma, Zijian Li, Jiayao Su, Shijie Xie, Peipei Cheng.

  Seneca Valley virus (SVV) infection leads to severe vesicular diseases in pigs, posing a significant threat to the global swine industry. Ferroptosis, a novel form of non-apoptotic cell death, is characterized by iron-dependent phospholipid peroxidation. However, the role of ferroptosis in SVV replication remains poorly understood. In this study, we demonstrate that SVV infection induces ferroptosis, as evidenced by lipid peroxidation, reactive oxygen species (ROS) accumulation, and glutathione (GSH) depletion. The GPX4 and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy are key contributors to ferroptosis induction. Furthermore, our findings reveal that the SVV 3 C proteinase (3Cpro) targets the GPX4 for degradation, thereby promoting ferroptosis. Simultaneously, the SVV 3D protein enhances the NCOA4-FTH1 interaction, leading to increased ferritin degradation and subsequent ferritinophagy. Notably, inhibition of ferroptosis significantly reduces SVV replication and its associated inflammatory effects. Collectively, these results elucidate the intricate molecular mechanisms underlying SVV-induced ferroptosis, highlighting the synergistic roles of 3Cpro and 3D in activating ferroptotic pathways and presenting potential targets for therapeutic intervention in SVV infections.

Keywords:  Ferritinophagy; Ferroptosis; GPX4; NCOA4; Seneca valley virus (SVV)

DOI:  https://doi.org/10.1007/s00018-025-05951-y
J Virol. 2025 Nov 10. e0117725

Pathogenic dengue virus TW2015 strain infection triggers anaerobic glycolysis and enhances mortality in diabetic mice.

Yi-Ping Kuo, Shih-Syong Dai, En-Ju Lin, Wann-Neng Jane, Wei-Hsiang Tsai, Wan-Ting Tsai, Zaida Nur Imana, Wan-Ju Tung, Yu-Siang Su, Chih-Feng Tien, Chia-Yi Yu, Chun-Hong Chen, Guann-Yi Yu.

  Dengue virus (DENV) strains with high pathogenicity and transmissibility pose significant public health challenges, especially in tropical and subtropical regions. Underlying conditions such as diabetes mellitus and renal diseases significantly increase the risk of severe dengue. The DENV-2 strain, responsible for a severe outbreak in Taiwan in 2015, exhibits enhanced pathogenicity and transmissibility in a mosquito-mouse transmission model. In this study, we demonstrated that pathogenic DENV infection leads to elevated lactate levels and hypoglycemia in mice, correlating with increased mortality in streptozotocin-induced diabetic models. In infected cells, pathogenic DENV induces rapid eIF2α phosphorylation, extensive ER membrane aggregation, disrupted calcium transfer to mitochondria, and mitochondrial dysfunction, which may contribute to excessive lactate production. Notably, inhibition of lactate production reduced viremia and mortality in mice. These findings highlight the role of metabolic dysregulation in DENV pathogenesis and provide insights into the mechanisms driving severe dengue, particularly in patients with underlying comorbidities.IMPORTANCEDENV is a mosquito-borne virus that can cause severe illness, particularly in tropical and subtropical regions. In 2015, a strain of DENV-2 caused a major outbreak in Taiwan with high mortality rates. People with conditions like diabetes or kidney disease were more likely to develop severe dengue. In our study, we found that this highly pathogenic virus caused mice to have high levels of lactate and low blood sugar before death. In diabetic mice, the virus caused even higher death rates. The virus impairs cellular energy production by disrupting communication between the endoplasmic reticulum and mitochondria, potentially leading to excessive lactate accumulation. Blocking lactate production helped reduce viremia and death rate. These findings suggest that the virus's impact on metabolism may play a role in severe illness, especially for people with pre-existing health issues.

Keywords:  PKR; dengue virus; diabetes; eIF2α; glycolysis; lactate; mitochondrial dysfunction

DOI:  https://doi.org/10.1128/jvi.01177-25
iScience. 2025 Nov 21. 28(11): 113750

Unraveling virus-host interactions: Current advances in viral lipidomics.

Belen Requena, Coral Barbas, Carolina Gonzalez-Riano.

  Viruses significantly alter host lipid metabolism to facilitate their replication, assembly, and immune evasion. Lipidomics, a mass spectrometry-driven field, enables the comprehensive profiling of virus-induced lipid remodeling and provides crucial insights into host-pathogen interactions. This review provides a comprehensive overview of cutting-edge lipidomic research in viral infections, focusing on studies published from January 2023 onwards. Emphasis is placed on recent advancements in understanding key respiratory viruses (e.g., SARS-CoV-2), bloodborne pathogens (HIV, HCV), and emerging viral threats such as West Nile or the Dengue viruses. We examine the latest analytical platforms, annotation techniques, and biological findings, highlighting how specific alterations in glycerophospholipid, sphingolipid, and sterol pathways reveal novel diagnostic and therapeutic opportunities. While challenges in standardization, isomer annotation, and clinical translation persist, emerging MS technologies and computational strategies promise to overcome these limitations. Integrating lipidomics with systems biology approaches will be crucial for advancing precision virology and developing next-generation antiviral therapies.

Keywords:  biological sciences; biotechnology; omics

DOI:  https://doi.org/10.1016/j.isci.2025.113750
Curr Opin Virol. 2025 Nov 10. pii: S1879-6257(25)00047-1. [Epub ahead of print]74 101497

A novel antiviral strategy by disrupting the equilibrium of virus-host calcium homeostasis.

Erwan Brémaud, Belinda L Spillings, Johnson Mak.

Calcium (Ca2+) homeostasis is essential for cellular signaling and protein trafficking. Viruses are comparatively simple organisms that leverage the availability of host cellular mechanisms for viral replication, including the manipulation of cellular Ca2+ dynamics-related processes. We review the dependence of HIV on cellular Ca2+ to promote viral replication, including stabilization of viral protein complexes in clinically latent HIV infected cells. We also discuss some of the general reliance of cellular Ca2+ homeostasis on viral propagation across several viruses. We discuss viral manipulations of cellular Ca2+ regulation for viral replication, specifically for viral assembly, complex stability, and disassembly. We close with an exploration of therapeutic opportunities via Ca2+ homeostasis disruption to mediate dysregulation of viral complex formation for viral peptide antigen presentation. Thereby, we aim to unlock a novel strategy to achieve an antiviral effect by modulating host-cell regulatory processes.

DOI: https://doi.org/10.1016/j.coviro.2025.101497
J Fish Dis. 2025 Nov 09. e70076

Grass Carp Catalase Inhibits Interferon Regulatory Factor-7 to Promote Grass Carp Reovirus Replication.

Jinglong Wang, Lu Yan, Junru Wang.

  Grass carp (Ctenopharyngodon idellus) is a vital species in China's aquaculture industry but is highly susceptible to grass carp haemorrhagic disease (GCHD) caused by the grass carp reovirus (GCRV). GCRV infection in Ctenopharyngodon idellus kidney cells (CIK) induces reactive oxygen species (ROS) overproduction, triggering oxidative stress. Catalase (Cat) is a crucial antioxidant enzyme that decomposes hydrogen peroxide (H2O2) into H2O and O2. In this study, we investigated and characterised the roles of CiCat in grass carp. CiCat is expressed ubiquitously in all examined tissues. Furthermore, when challenged with GCRV, its expression levels are significantly upregulated. Fluorescence analysis revealed that CiCat exhibits a widespread cellular distribution, while GCRV infection enhances its aggregation and co-localisation with mitochondria (Mit) and endoplasmic reticulum (ER). Overexpression of CiCat eliminates both H2O2 and GCRV-induced ROS, decreases the expression of antioxidant enzymes and promotes GCRV replication. Further research showed that overexpression of interferon regulatory factor-7 (IRF-7) inhibits GCRV replication, but CiCat reduces IRF-7 expression. In summary, CiCat promotes GCRV replication by reducing CiIRF-7 expression.

Keywords:  catalase; grass carp reovirus; interferon regulatory factor‐7

DOI:  https://doi.org/10.1111/jfd.70076
J Virol. 2025 Nov 11. e0156325

Ceramide synthase 4 interferes with replication of influenza virus but is downregulated by infection.

Kwang Il Jung, Chuan Xia, Savannah McKenna, Ying He, Vijayamahantesh Vijayamahantesh, Jennifer J Wolf, Bumsuk Hahm.

  Influenza continues to pose a serious threat to humans. Influenza-host interaction is incompletely understood, requiring identification of host factors that regulate viral pathogenicity. Ceramide synthases (CerSs) are responsible for producing and controlling ceramide levels within cells. Ceramides are structural and signaling sphingolipid components that mediate various biological functions and affect the infectivity of multiple viruses. However, the role of CerSs during virus infections remains unclear. In this study, we investigated the possible function of CerSs in host defense against influenza virus infection. Cells stably expressing CerS4 poorly supported influenza virus replication, whereas CerS1 did not affect replication. Transient overexpression of CerS4 also impaired the efficient production of viral proteins as well as infectious progeny viruses. In support of these results, knockdown of endogenous CerS4 in cells enhanced virus replication. Intriguingly, CerS4 impeded virus-induced activation of cellular c-Jun N-terminal kinase (JNK), which interfered with influenza viral replication. On the other hand, influenza virus infection was shown to induce CerS4 ubiquitination and downregulation, which could limit the antiviral activity of CerS4. Collectively, these findings reveal a new function of CerS4 that restricts influenza virus infection and provides valuable insights into influenza-host defense interactions.IMPORTANCESeasonal influenza causes serious public health problems in the world with substantial annual morbidity and mortality. Further, there have been persistent concerns about potential development of an influenza pandemic. Current antiviral drugs are limited in their efficacy, especially due to the rapid emergence of drug-resistant variants. Host protein-directed therapy is an alternative or complementary approach to broadly controlling influenza virus infections but requires a deeper understanding of influenza-host interplay. Host ceramide synthase 4 regulates the level of ceramides that possess both structural and signaling mediator functions. Our study reveals that ceramide synthase 4 displays an antiviral activity against influenza virus infection by regulating JNK activation. However, influenza virus triggers degradation of ceramide synthase 4, which could favor virus replication. The findings advance our knowledge about the ceramide network interaction with influenza and provide a framework for developing a host-targeted therapy to cure influenza.

Keywords:  JNK regulation; ceramide synthase 4; influenza virus; influenza-host interaction

DOI:  https://doi.org/10.1128/jvi.01563-25
Front Vet Sci. 2025 ;12 1674259

Calycosin inhibits porcine reproductive and respiratory syndrome virus replication and activates RIG-I/IRF3 signaling pathway.

Yafei Chang, Zhaopeng Li, Mengqi Wang, Kanglei Pei, Xiaobo Chang, Jinyou Ma.

  Porcine reproductive and respiratory syndrome virus (PRRSV), the causative pathogen of PRRS, remains one of the most important pathogens threatening the global pig industry. Due to the genetic diversity of PRRSV, the existing commercially vaccines cannot completely protect pigs from PRRSV infection. Flavonoid compounds play an important role in inhibiting viral replication. In this study, we found that calycosin, a natural active compound isolated from astragalus, could inhibit PRRSV replication regardless of whether calycosin was added pre-, co-, or post-PRRSV infection in vitro. Furthermore, coincubation of calycosin with PRRSV showed a better inhibitory effect compared to separate incubation, and calycosin mainly inhibited virus replication, assembly and release stages. Importantly, calycosin enhanced the antiviral immunity, as shown by the increased expression of IFN-β and ISG56. Subsequently, we discovered that calycosin promoted the expression of RIG-I and MAVS, and induced the phosphorylation and nuclear translocation of IRF3 during PRRSV infection. Collectively, calycosin could markedly inhibit PRRSV replication and activate the RIG-I/IRF3 signaling pathway. These data contribute to understanding the role of calycosin in PRRSV replication, and may provide valuable insights for the development of future antiviral strategies.

Keywords:  IRF3; PRRSV; RIG-I; antiviral activity; calycosin

DOI:  https://doi.org/10.3389/fvets.2025.1674259
Sci Rep. 2025 Nov 10. 15(1): 39207

Baicalin inhibits infectious bronchitis virus replication via MAVS-dependent interferon-β upregulation and mitochondrial function preservation.

Jiongjie He, Huilin Guo, Ling Wang, Shengyi Wang.

  The inhibitory effect of baicalin on infectious bronchitis virus (IBV) replication is closely related to expression of the mitochondrial antiviral signaling protein (MAVS) in chicken embryonic kidney (CEK) cells. Baicalin significantly upregulated MAVS expression dose-dependently and maintained mitochondrial function through MAVS. Baicalin increased expression of mitofusin-1 (Mfn1), anti-apoptotic mitochondrial import receptor subunit TOM70 (TOM70), voltage-dependent anion channel 1 (VDAC1), autophagy-related 5 (Atg5), and autophagy-related 12 (Atg12). Overexpression of Mfn1, VDAC1, TOM70, Atg5, and Atg12 enhanced baicalin-mediated interferon-β (IFN-β) expression, while knockdown of Mfn1, TOM70, VDAC1, TRADD, Atg5, or Atg12 significantly decreased IFN-β protein levels. In MAVS-knockdown cells, overexpression of Mfn1, mitofusin-2 (Mfn2), VDAC1, TNFR1-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), Atg5, and Atg12 did not affect baicalin-mediated IFN-β expression. Thus, baicalin promotes mitochondrial fusion, permeability, metabolism, and autophagy. Baicalin upregulates IFN-β via Mfn1, VDAC1, TOM70, Atg5, and Atg12 dependent on MAVS. Moreover, baicalin inhibits key cytokines in the NF-κB pro-inflammatory pathway.

Keywords:  Baicalin; Infectious bronchitis virus; Interferon-β; Mitochondrial antiviral signaling gene (MAVS); Mitochondrial function; NF-κB pro-inflammatory pathway

DOI:  https://doi.org/10.1038/s41598-025-16941-2
Mol Biomed. 2025 Nov 10. 6(1): 105

Itaconate reduces viral endocytosis by targeting Cys128 of the adaptor-related protein complex 1 gamma 1 subunit in the host, providing a novel target for antiviral drug development.

Xinqi Deng, Heng Chen, Zhixing Huang, Rongge He, Qinling Rao, Luni Xu, Zijian Xu, Naixuan Zhao, Yeqing Peng, Muxuan Li, Xi Liu, Tao Ma, Xiaolan Cui, Chunguo Wang.

  Traditional antiviral strategies primarily rely on vaccines and virus protein-targeting drugs, which adopt a virus-targeting approach. However, the rapid mutation of viruses often leads to vaccine failure and drug resistance, highlighting the limitations of these conventional methods. Consequently, the development of novel broad-spectrum, host-targeting antiviral strategies has become a major research focus. Itaconate, an endogenous immunomodulatory metabolite, inhibits viral replication via post-translational modifications; however, its mechanism in suppressing viral endocytosis remains unclear. This study demonstrates that itaconate inhibits viral endocytosis by covalently modifying the Cys128 site of the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), thereby providing a new target for host-directed antiviral drug development. It was found that itaconate binds to AP1G1 at Cys128, impairing its interaction with clathrin, which inhibits clathrin-mediated viral particle uptake and reduces cellular susceptibility to infection (i.e., the likelihood of cells being infected by viruses and undergoing infection). Furthermore, the natural product Licochalcone B was identified as targeting the same site as itaconate. In both BEAS-2B cell models and mouse infection models, Licochalcone B reduced pulmonary viral loads by over 95%. This study is the first to propose and validate the feasibility of inhibiting broad-spectrum viral infection by targeting AP1G1, elucidating a novel molecular mechanism of itaconate-mediated regulation, offering a new target for broad-spectrum antiviral drug development, and identifying Licochalcone B as a promising broad-spectrum antiviral agent.

Keywords:  AP1G1; Clathrin; Itaconate; Post-translational modification; Virus

DOI:  https://doi.org/10.1186/s43556-025-00348-6
PLoS Pathog. 2025 Nov 11. 21(11): e1013694

Epstein-Barr virus-transformed B-cells from a Hypoxia model of the germinal center requires external unsaturated fatty acids.

Larissa Havey, Haixi You, Huimin Xian, John M Asara, Rui Guo.

Epstein-Barr virus (EBV) drives over 200,000 cancer cases annually, including diffuse large B-cell lymphoma, Burkitt lymphoma, and classic Hodgkin lymphoma-malignancies that frequently originate from germinal centers (GCs), which are physiologically hypoxic (O2 < 1%). However, conventional transformation models are typically conducted under 21% O2-an artificial condition that fails to replicate the hypoxic GC microenvironment and may obscure critical metabolic vulnerabilities that are therapeutically targetable. Therefore, therapeutic targets identified under 21% O2 conditions may not fully translate to the hypoxic environment of lymphoid tissues, which could limit their effectiveness in vivo. To overcome these limitations, we developed an ex vivo model of EBV-driven B-cell transformation under 1% O2, mimicking GC hypoxia. Under 1% O2, EBV efficiently transformed primary human B cells, inducing hallmark oncogenic programs and activating super-enhancers at key loci including MYC and IRF4. Multi-omic profiling revealed a distinct hypoxia-adapted metabolic state, characterized by suppressed fatty acid synthesis, enhanced glycolysis and glycerophospholipid metabolism, and increased triglyceride storage in lipid droplets. These adaptations alleviate lipotoxic stress and maintain redox balance but render transformed cells highly dependent on external unsaturated fatty acids. Inhibition of triglyceride synthesis using the DGAT1 inhibitor A922500 selectively impaired proliferation and survival of EBV-transformed B cells under GC-like hypoxia. These findings define key metabolic dependencies shaped by the hypoxic GC microenvironment and establish a physiologically relevant platform for studying EBV-driven B-cell transformation. Our work highlights the importance of modeling physiological oxygen tension and suggests that targeting lipid uptake and storage pathways may offer new therapeutic opportunities for halting EBV transformation with hypoxic tissue niches.

DOI: https://doi.org/10.1371/journal.ppat.1013694
mBio. 2025 Nov 10. e0255425

Human-specific activation of the DUX4-SLC34A2 axis by herpesviruses suppresses antiviral innate immunity.

Ming Gao, Xi Cheng, Chuchu Zhang, Jiali Ma, Xuezhang Tian, Shaowei Wang, Xiaoyu Xie, Yunhong Zhong, Siyuan Wang, Pinghui Feng, Junjie Zhang.

  Viral pathogens employ diverse strategies to antagonize host antiviral innate immune defenses. However, the human-specific nature of viral immune evasion mechanisms remains poorly understood. Here, we report that herpesvirus infection selectively activates the embryonic transcription factor DUX4 in human but not murine cells. DUX4 drives the expression of the phosphate transporter SLC34A2, which plays a critical role in suppressing antiviral innate immunity. Mechanistically, SLC34A2 increases intracellular phosphate levels, thereby suppressing the activity of multiple immune and stress-related kinases, including TBK1. Genetic disruption of DUX4 or SLC34A2 restores innate immune activation and enhances interferon responses. Our findings reveal a previously unrecognized, phosphate-mediated immunosuppressive mechanism and define a human-specific transcriptional circuit exploited by herpesviruses to antagonize innate immunity.IMPORTANCEHerpesviruses are notorious for their ability to evade host immune responses, yet the mechanisms underlying human-specific immune evasion remain poorly understood. This study identifies a previously unrecognized viral immune evasion strategy by which herpesviruses suppress antiviral immunity in human cells but not murine cells. We demonstrate that herpesvirus infection induces the expression of the embryonic transcription factor DUX4, which subsequently activates its downstream target, SLC34A2, a phosphate transporter. DUX4-SLC34A2 activation reprograms infected cells toward an embryonic-like transcriptional profile, creating an environment conducive to viral replication. Importantly, we show that SLC34A2 increases intracellular phosphate levels, thereby suppressing the activity of multiple immune and stress-related kinases, including TBK1. Our findings reveal a previously unrecognized phosphate-mediated regulation of antiviral immunity, providing insights into viral-host interactions and highlighting therapeutic targets for enhancing antiviral defense.

Keywords:  antiviral innate immunity; herpesvirus; immune evasion; phosphate

DOI:  https://doi.org/10.1128/mbio.02554-25