bims-mevinf 2025-08-17 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–08–17
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity.
Newcastle disease virus exploits the phospholipid flippase ATP11c/CDC50A complex to promote viral infection.
Targeting sphingolipid metabolism: inhibition of neutral sphingomyelinase 2 impairs coronaviral replication organelle formation.
Pestivirus bovine viral diarrhea virus infection triggers lipophagy through the AMPK-PNPLA2/ATGL signaling pathway to promote viral replication.
The diverse interaction of metabolism, immune response, and viral pathogens.
Vaccinia virus modulates the redox environment by inhibiting reactive oxygen and nitrogen species with increased activity of endogenous antioxidant enzymes.
25HC Depleted PMs-Accessible Cholesterol to Restrict SFTSV Entry and Infectious-EVs Mediated Infection.
25-Hydroxy cholesterol effectively inhibits Japanese encephalitis virus infection in a cellular model.
Vaginal metabolic profiling reveals biomarkers characteristics of high-risk HPV infection and cervical lesions.
eIF2α Kinases Involve in the Regulation of VSV Replication Through CHOP in SMMC7721 Cells.

Int J Mol Sci. 2025 Jul 30. pii: 7346. [Epub ahead of print]26(15):

Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity.

Martin A Zenov, Dmitry V Yanvarev, Olga N Ivanova, Ekaterina A Denisova, Mikhail V Golikov, Artemy P Fedulov, Roman I Frykin, Viktoria A Sarkisova, Dmitry A Goldstein, Peter M Chumakov, Anastasia V Lipatova, Alexander V Ivanov.

  Poliovirus represents an oncolytic agent for human glioblastoma-one of the most aggressive types of cancer. Since interference of viruses with metabolic and redox pathways is often linked to their pathogenesis, drugs targeting metabolic enzymes are regarded as potential enhancers of oncolysis. Our goal was to reveal an imprint of poliovirus on the metabolism of glioblastoma cell lines and to assess the dependence of the virus on these pathways. Using GC-MS, HPLC, and Seahorse techniques, we show that poliovirus interferes with amino acid, purine and polyamine metabolism, mitochondrial respiration, and glycolysis. However, many of these changes are cell line- and culture medium-dependent. 2-Deoxyglucose, the pharmacologic inhibitor of glycolysis, was shown to enhance the cytopathic effect of poliovirus, pointing to its possible repurposing as an enhancer of oncolysis. Inhibitors of polyamine biosynthesis, pyruvate import into mitochondria, and fatty acid oxidation exhibited antiviral activity, albeit in a cell-dependent manner. We also demonstrate that poliovirus does not interfere with the production of superoxide anions or with levels of H2O2, showing an absence of oxidative stress during infection. Finally, we showed that a high rate of poliovirus replication is associated with fragmentation of the mitochondrial network, pointing to the significance of these organelles for the virus.

Keywords:  Plasmax; glioblastoma; metabolism; oncolytic viruses; poliovirus; polyamines; respiration; seahorse

DOI:  https://doi.org/10.3390/ijms26157346
J Biol Chem. 2025 Aug 12. pii: S0021-9258(25)02435-4. [Epub ahead of print] 110584

Newcastle disease virus exploits the phospholipid flippase ATP11c/CDC50A complex to promote viral infection.

Dandan Zhang, Yuechi Hou, Xusheng Qiu, Yang Qu, Yingjie Sun, Cuiping Song, Ying Liao, Chan Ding, Lei Tan.

Newcastle disease virus (NDV), a highly contagious avian pathogen, causes significant economic losses in the poultry industry. As an enveloped, negative-sense single-stranded RNA virus, NDV infection and replication are intricately linked to host lipid metabolism, particularly phospholipids like phosphatidylserine (PS). PS asymmetry across the plasma membrane (PM), maintained by phospholipid flippases such as the ATP11c/CDC50A complex, is crucial for cellular homeostasis but can be exploited by viruses. However, the specific roles of PS and its dynamic regulation by flippases during NDV infection remain unclear. In this study, we investigated how NDV utilizes host PS and the ATP11c/CDC50A complex to facilitate its life cycle. We found that the phospholipid flippase ATP11c/CDC50A complex maintains membrane asymmetry by translocating PS to the inner leaflet, while NDV subverts this process by hijacking envelope-associated PS for viral entry and budding. CRISPR/Cas9-mediated ATP11c knockout reduced PS flipping efficiency, impaired NDV replication, and disrupted progeny virion release. Notably, CDC50A mutations (D193G/K319E) compromised ATP11c activity, reducing PS redistribution by 60% (p<0.05), highlighting its essential role in flippase function. Mechanistically, NDV-induced apoptosis triggered PS externalization, which enhanced Matrix (M) protein clustering at PS-rich membrane domains, significantly increased virus-like particle (VLP) production (p<0.05). The results reveal that NDV exploits host ATP11c/CDC50A-mediated maintenance of inner-leaflet PS asymmetry to anchor M protein oligomerization at the PM during replication. These findings fundamentally advance our understanding of viral pathogenesis by elucidating how NDV subverts host lipid homeostasis to fuel its replication cycle.

DOI: https://doi.org/10.1016/j.jbc.2025.110584
mBio. 2025 Aug 14. e0008425

Targeting sphingolipid metabolism: inhibition of neutral sphingomyelinase 2 impairs coronaviral replication organelle formation.

Florian Salisch, Fabian Schumacher, Ulrich Gärtner, Burkhard Kleuser, John Ziebuhr, Christin Müller-Ruttloff.

  Many plus-strand RNA viruses, including coronaviruses, orchestrate the formation of specialized replication organelles in the cytoplasm of infected cells by specific membrane-associated viral nonstructural proteins (nsp's). This process involves a massive reorganization of intracellular membrane compartments and is thought to depend on a specific set of cellular enzymes that synthesize or modify cellular lipids. Here, we investigated the potential role(s) of specific sphingolipids and related enzymes in coronavirus replication. We observed in cells infected with three different coronaviruses a comparable increase in global ceramide levels, whereas sphingomyelin levels were reduced, suggesting an enhanced conversion of sphingomyelin to ceramide by sphingomyelinases. To test this hypothesis, we targeted cellular sphingomyelinases using pharmacological and genetic approaches. The data obtained in these experiments led us to conclude that neutral sphingomyelinase 2 plays a critical role in an early (but not the entry) step of coronavirus replication in Huh-7-ACE2 cells. Furthermore, neutral sphingomyelinase 2 inhibited the formation of viral replication organelles, indicating the involvement of ceramide in the formation of these membrane structures. We also confirmed colocalization of neutral sphingomyelinase 2 and ceramide, but not sphingomyelin, with replication organelles that were produced in coronavirus-infected cells or induced by co-expression of coronavirus nsp3 and nsp4. A colocalization of ceramides with coronaviral replication organelles could be consistently demonstrated for different epithelial cell systems using genetically diverse coronaviruses, describing potential cell- and virus-type independence.
IMPORTANCE: Coronaviruses are enveloped plus-strand RNA viruses with a broad host range, including humans. Human coronaviruses are not only associated with endemic, mild upper respiratory tract infections but also have pandemic potential and can be associated with a severe disease burden. The recent SARS-CoV-2 pandemic especially highlighted the urgent need to identify ideal broad-spectrum and host-targeted antiviral strategies. Since lipids are involved in every step of viral replication, we compared changes in the sphingolipid metabolism of cells infected with three different coronaviruses to identify similarities and related cellular enzymes involved in facilitating viral replication. We observed increased ceramide levels while sphingomyelin levels decreased, suggesting enhanced sphingomyelin-to-ceramide conversion by cellular sphingomyelinases upon infection. Impairment of neutral sphingomyelinase 2 reduced viral replication and the formation of virus-induced membranous replication organelles. Furthermore, we found that neutral sphingomyelinase 2 and its product ceramide were associated with viral replication organelles. Ceramides consistently appeared to be integral lipid building blocks of replication organelles across different human pathogenic coronaviruses and cell types. In conclusion, our study provides new insights into novel potentially conserved druggable sphingolipid-related host factors involved in coronaviral replication, offering potential new targets for antiviral therapies against newly emerging coronaviruses.

Keywords:  HCoV-229E; coronavirus; lipid metabolism; replication organelles; sphingomyelinase; viral replication

DOI:  https://doi.org/10.1128/mbio.00084-25
Autophagy. 2025 Aug 11.

Pestivirus bovine viral diarrhea virus infection triggers lipophagy through the AMPK-PNPLA2/ATGL signaling pathway to promote viral replication.

Yingying Ma, Wenlu Fan, Yixin Wang, Jing Wang, Yuan Li, Xinyue Xia, Haiyue Zhu, Yue Lu, Guizhi Hou, Yujia Wang, Xinyuan Qiao, Houhui Song, Yigang Xu.

  Macroautophagy/autophagy facilitates the catabolic process by degrading lipids within lysosomes, thereby maintaining cellular energy homeostasis. However, the precise mechanism by which bovine viral diarrhea virus (BVDV) induces autophagy to reprogram lipid metabolism remains unclear. In this study, we determined that BVDV infection depletes ATP and simultaneously induces the reprogramming of intracellular lipid metabolism. We also observed that BVDV infection promotes autophagy-dependent processing of lipid droplets and triglycerides, leading to the release of free fatty acids. The ATP content in BVDV-infected cells was reduced, resulting in an increased AMP:ATP ratio and subsequent phosphorylation of AMP-activated protein kinase (AMPK). Mechanistically, BVDV infection activates AMPK, subsequently enhancing lipophagy and facilitating viral replication. Our study further elucidates that PNPLA2/ATGL (patatin like domain 2, triacylglycerol lipase) may function as a downstream effector in the AMPK pathway, promoting lipophagy during BVDV infection. The BVDV nonstructural protein NS5A was found to induce autophagy via an AMPK-PNPLA2 pathway. Immunoprecipitation assays demonstrated that NS5A interacts with BECN1 and PNPLA2. These findings suggest that BVDV infection modulates lipophagy by regulating the AMPK-PNPLA2 pathway, thereby mobilizing energy for its replication. Overall, our data suggest that targeting the AMPK-PNPLA2 pathway could serve as a novel host-directed antiviral strategy, offering significant insights for the development of innovative BVDV vaccines and therapeutic drugs.

Keywords:  AMPK-PNPLA2 pathway; BVDV; NS5A protein; lipophagy; viral replication

DOI:  https://doi.org/10.1080/15548627.2025.2546934
Front Immunol. 2025 ;16 1619926

The diverse interaction of metabolism, immune response, and viral pathogens.

Toshio Kanno, Keisuke Miyako, Yusuke Endo.

  During viral infections, both innate and adaptive immune responses are activated to establish host defense mechanisms. In innate immunity, the STING and MAVS pathways, which recognize viral genomes, play a central role in inducing type I interferons (IFN-I), a group of antiviral cytokines. Concurrently, adaptive immune responses, particularly those mediated by T cells, contribute to viral clearance and the establishment of immune memory through the recognition of viral antigens. Recently, numerous studies have highlighted the impact of alterations in lipid metabolism on host immune cells during viral infections. Because viruses lack the ability to synthesize their own lipid membranes, they rely on host lipid metabolic pathways to support their replication. In addition, IFN-I signaling has been shown to suppress the expression of lipid metabolic genes and promote the generation of antiviral lipids. Furthermore, following viral infection, both innate and adaptive immune cells rewire various metabolic pathways, including lipid metabolism, glycolysis, the tricarboxylic acid cycle, and amino acid metabolism, to mount effective antiviral responses. This review focuses on recent advances in our understanding of lipid metabolic reprogramming during viral infection at both the cellular and systemic levels, and how such metabolic changes shape and regulate immune responses.

Keywords:  SCD2; T cells; cGAS-STING; immunometabolism; lipid metabolism; pathogen nucleotide sensor; virus infections; virus lipid

DOI:  https://doi.org/10.3389/fimmu.2025.1619926
Sci Rep. 2025 Aug 13. 15(1): 29771

Vaccinia virus modulates the redox environment by inhibiting reactive oxygen and nitrogen species with increased activity of endogenous antioxidant enzymes.

Marília Bueno da Silva Menegatto, Ariane Coelho Ferraz, Rafaela Lameira Souza Lima, Pedro Henrique Guimarães, Oluwashola Samuel Ola-Olu, Pedro Alves Machado-Junior, Wellington Carvalho Malta, Thaís de Fátima Silva Moraes, Frank Silva Bezerra, Breno de Mello Silva, José Carlos de Magalhães, Jordana Grazziela Alves Coelho Dos Reis, Flávio Guimarães da Fonseca, Giliane de Souza Trindade, Erna Geessien Kroon, Cintia Lopes de Brito Magalhães.

  The vaccinia virus (VACV) is the most studied and well-characterised member of the Poxviridae family. However, the mechanisms through which it modulates redox homeostasis in host cells remain unclear. Although oxidative stress, which is marked by elevated levels of reactive species, contributes to the pathogenesis of many viral infections, poxviruses may adopt distinct strategies. VACV has redox effector proteins that are released into the cytosol when the virus penetrates the host cell. This study demonstrates for the first time that VACV infection leads to the activation of the nuclear factor erythroid 2 (Nrf2)/antioxidant response element pathway, a key regulator of cellular antioxidant responses, a mechanism not previously described for any poxvirus. Using BSC-40 cells, we observed that VACV significantly reduced reactive oxygen and nitrogen species levels, downregulated inducible nitric oxide synthase, and enhanced the activity of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase. This antioxidant shift is correlated with increased Nrf2 activity and the upregulation of its downstream targets. This virus-induced antioxidant state may be an immunomodulatory mechanism that facilitates viral replication by dampening host defence. Thus, our findings expand the current understanding of virus-host interactions in poxvirus infections.

Keywords:  Antioxidant; Poxviruses; Redox homeostasis; Vaccinia virus

DOI:  https://doi.org/10.1038/s41598-025-14433-x
FASEB J. 2025 Aug 31. 39(16): e70839

25HC Depleted PMs-Accessible Cholesterol to Restrict SFTSV Entry and Infectious-EVs Mediated Infection.

Rui Zhang, Linrun Li, Siyu Li, Shengxia Yin, Min Cheng, Na Jing, Jie Li, Zhiwei Wu, Chao Wu.

  Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel tick-borne phlebitis virus of Bunyaviridae, newly named as Banda virus, characterized by high fever, thrombocytopenia, and leukopenia with high case fatality. Currently, no specific antiviral drugs are available to treat patients. Here, we report a natural lipid metabolite 25-Hydroxycholesterol (25HC) that inhibited SFTSV entry by activating the activity of acetyl-CoA-cholesterol acyltransferase (ACAT), a lipid metabolism enzyme, affecting the accessible cholesterol translocation between the cytoplasm and plasma membranes (PMs). We also found that 25HC could inhibit the extracellular vesicles carrying virions into target cells, thus preventing the vesicles from mediating virus spread. In short, 25HC reduced the PMs-accessible cholesterol through modulating lipid metabolism, thereby inhibiting the double infection of cells by virions and infectious EVs, and potentially reducing the efficiency of SFTSV dissemination.

Keywords:  25HC; PMs‐cholesterol; SFTSV; vesicle‐mediated virus transmission; virus entry

DOI:  https://doi.org/10.1096/fj.202403337RR
Biochem Biophys Res Commun. 2025 Aug 09. pii: S0006-291X(25)01182-9. [Epub ahead of print]780 152467

25-Hydroxy cholesterol effectively inhibits Japanese encephalitis virus infection in a cellular model.

Km Archana, Bushra Qazi, Babita Bohra, Raj Kamal Tripathi, Sourav Haldar.

  The Japanese encephalitis virus (JEV) is a mosquito-borne, enveloped flavivirus that causes acute encephalitis. Although JEV is increasingly recognized as a global threat, there is currently no FDA-approved treatment available for JEV. 25-hydroxycholesterol (25-HC) is an oxysterol produced through the oxidation of cholesterol, a process catalyzed by cholesterol 25-hydroxylase (CH25H), which is an interferon-stimulated gene that is upregulated during viral infections. In this study, we report for the first time that 25-HC effectively prevents JEV infection in cells. Our results show that 25-HC inhibits JEV infection in Vero cells with an IC50 of ∼4.18 μM, while displaying no cell toxicity (CC50 > 50 μM). In addition, we show that the RNA level of the JEV envelope (E) protein exhibits a dose-dependent reduction in the presence of 25-HC, which is further supported by the concomitant decrease of the E protein expression. We surmise that the anti-JEV properties of 25-HC stem from its effects on the host plasma membrane organization and dynamics by modulating membrane cholesterol level, which may impair the entry and fusion of JEV. Given the antiviral effects of 25-HC against Zika and Dengue viruses, our findings suggest that 25-HC could be a promising candidate for developing broad-spectrum anti-flaviviral therapeutics.

Keywords:  25-Hydroxycholesterol; Cholesterol; Flavivirus; Japanese encephalitis virus; Membranes

DOI:  https://doi.org/10.1016/j.bbrc.2025.152467
J Obstet Gynaecol Res. 2025 Aug;51(8): e70035

Vaginal metabolic profiling reveals biomarkers characteristics of high-risk HPV infection and cervical lesions.

Xiaoling Huang, Xiaoge Li, Sijing Li, Jin Wu, Zhaoning Duan, Ming Luo, Ying Jia.

   OBJECTIVE: This study aimed to identify potential biomarkers in high-risk human papillomavirus (HR-HPV) infections and related cervical lesions through the analysis of vaginal metabolic profiles.
PATIENTS AND METHODS: Forty cervicovaginal secretion samples were collected from healthy individuals, HR-HPV-positive individuals, low-grade squamous intraepithelial lesion patients, high-grade squamous intraepithelial lesion patients, and cervical cancer (CC) patients. All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Metabolites with significant differences were identified using the variable importance in projection (VIP > 1) derived from the orthogonal least partial squares discriminant analysis (OPLS-DA) model and the p-value (p < 0.05) of the Student's t test. Utilizing hierarchical cluster analysis and receiver operating characteristic curve analysis, the optimal biomarkers were identified, and the diagnostic potential of these biomarkers was evaluated. Significantly enriched pathways of the differential metabolites were explored using metabolic pathway analysis.
RESULTS: LC-MS analysis of the vaginal metabolomic profiles revealed unique molecular characteristics of different states of HR-HPV infection. Based on persistent HR-HPV infection, 3-Isochromanone increased, and DG(2:0/5-iso PGF2VI/0:0) and (4R,5S,7R,11x)-11,12-Dihydroxy-1(10)-spirovetiven-2-one 12-glucoside decreased (p < 0.05) with the aggravation of cervical lesions, suggesting their potential as biomarkers to predict various stages of cervical lesions. Additionally, analysis of metabolic pathway enrichment for differential metabolites identified the phenylalanine, tyrosine, and tryptophan biosynthesis pathways as the key metabolic pathways in the progression of cervical lesions.
CONCLUSION: By measuring the metabolome of vaginal secretions, specific metabolites can effectively distinguish persistent HR-HPV infections and different grades of cervical lesions, which may become an important means for the early screening and diagnosis of CC.

Keywords:  biomarkers; cervical cancer; high‐risk HPV; metabolomics; precancerous lesions

DOI:  https://doi.org/10.1111/jog.70035
J Med Virol. 2025 Aug;97(8): e70548

eIF2α Kinases Involve in the Regulation of VSV Replication Through CHOP in SMMC7721 Cells.

Runxin Luan, Yiyuan Shang, Mingjie Chen, Senyue Li, Rong Zhang, Shengzhen Sun, Panlin Wang, Dan Song, Yanan Zhang, Xiangchen Li, Yongshu Wu.

  Previous studies have shown that eIF2α kinases involved in viral replication through eIF2α phosphorylation upon vesicular stomatitis virus (VSV) infection. The oncotherapy approach of VSV is based on its inducing controlled apoptosis in tumor cells. In this study, we explorated the role of eIF2α kinases in VSV replication and CHOP expression in SMMC7721 cell lines. We found that three eIF2α kinases involved in VSV replication, PERK inhibited viral replication through eIF2α phosphorylation, both PKR and GCN2 initiated CHOP expression to favor viral replication at late stage, and HRI had no effect on VSV replication. These findings confirmed that eIF2α kinases initiate an integrated response and regulate viral replication to restore cellular homeostasis upon viral infection. The activation of CHOP expression may facilitate the release and spread of viral progeny, enrich the characteristics of VSV-induced apoptosis through CHOP expression, and provide a strategy for cancer therapy.

Keywords:  CHOP; ISR; eIF2α kinases; oncolytic virus; vesicular stomatitis virus (VSV)

DOI:  https://doi.org/10.1002/jmv.70548