bims-mevinf 2025-09-07 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–09–07
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

The bittersweet link between glucose metabolism, cellular microenvironment and viral infection.
Pseudorabies virus induces ferroptosis by disrupting iron homeostasis through activation of TfR1 and ferritinophagy.
Babaco mosaic virus BabMV induces defense metabolite production in papaya plants (Carica papaya).
Decoding blood fatty acids in Crimean-Congo hemorrhagic fever.
Comprehensive Analysis of Liver Transcriptome and Metabolome Response to Oncogenic Marek's Disease Virus Infection in Wenchang Chickens.
Comparative profiling of splenic phospholipid and sphingolipid during acute infection.
Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape.
Glycosylphosphatidylinositol biosynthesis functions as a conserved host defense pathway against coronaviruses via regulation of LY6E.
ARRDC4-mediated glycolysis enhances innate immunity to influenza A virus through fructose-1,6-bisphosphate.

Virulence. 2025 Dec;16(1): 2554302

The bittersweet link between glucose metabolism, cellular microenvironment and viral infection.

Xueao Liu, Li Chen, Honglin Niu, Yuhan Chen, Peiyao Chen, Lei Liu, Rui Wu.

  Viral particles and proteins released during infection profoundly reshape the cellular microenvironment by disrupting host signaling, triggering inflammation, and modulating immune responses. Glucose metabolism, a critical hub for energy production and biosynthesis, is highly susceptible to viral reprogramming. This review summarizes recent findings showing that diverse viruses, including influenza virus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and enteroviruses, manipulate glucose metabolic pathways to promote replication and evade immune surveillance. Specifically, viruses modulate glycolytic flux, alter the activity of key metabolic enzymes such as hexokinase (HK) and pyruvate kinase, and interfere with signaling networks like PI3K/Akt/mTOR and AMPK. These metabolic alterations further impact the immune landscape by regulating cytokine production, immune cell activation, and antiviral responses. Our analysis highlights a bidirectional interaction: while viruses hijack host glucose metabolism to favor their survival, metabolic changes also generate host-derived antiviral responses. This review highlights the bidirectional crosstalk between metabolic remodeling and microenvironmental changes during viral infection, underscoring the potential of metabolism-based antiviral strategies. A deeper understanding of these mechanisms may inform the development of more effective and targeted interventions against viral diseases.

Keywords:  Glucose metabolism; cellular microenvironment; immune response; metabolic reprogramming; viral infection

DOI:  https://doi.org/10.1080/21505594.2025.2554302
J Virol. 2025 Sep 02. e0097425

Pseudorabies virus induces ferroptosis by disrupting iron homeostasis through activation of TfR1 and ferritinophagy.

Zicheng Ma, Lei Guo, Ran Ji, Zhe Sun, Jingyi Wang, Yang Yan, Kesen Liu, Hanhua Zhang, Xingya Wang, Chengyue Wu, Lin Lian, Wandi Cao, Juan Bai, Ping Jiang, Xing Liu.

  Programmed cell death (PCD) refers to a regulated cellular process involving a cascade of biochemical reactions and molecular mechanisms, commonly including apoptosis, necroptosis, and pyroptosis. Ferroptosis is a recently identified form of PCD distinguished by its dependence on iron. Emerging evidence underscores the significance of ferroptosis in viral infections; however, its role in Pseudorabies virus (PRV) infection, an enveloped double-stranded DNA virus belonging to the Alphaherpesvirinae subfamily, remains poorly understood. Here, we demonstrate that PRV infection induces multiple forms of PCD, including ferroptosis, which is characterized by mitochondrial shrinkage, lipid peroxidation, ferrous iron (Fe²+) accumulation, and elevated levels of reactive oxygen species (ROS). Ferroptosis facilitates PRV replication, with iron overload playing a crucial role. Mechanistically, we show that transferrin receptor 1 (TfR1) and ferritinophagy are involved in PRV-induced iron overload. Specifically, PRV infection upregulates TfR1 expression via hypoxia-inducible factor-1β (HIF-1β) and promotes its translocation to the cell membrane through Rab11a, thereby enhancing the cellular import of extracellular ferric iron (Fe³+). In parallel, PRV activates ferritinophagy to degrade ferritin heavy chain 1 (FTH1) via selective autophagy receptors, nuclear receptor coactivator 4 (NCOA4) and Tax1-binding protein 1 (TAX1BP1), further contributing to intracellular iron accumulation. Altogether, these findings demonstrate that PRV induces ferroptosis by disrupting iron homeostasis through TfR1 activation and ferritinophagy induction, providing novel insights into the pathogenesis of PRV and other herpesviruses.IMPORTANCEFerroptosis is an iron-dependent form of non-apoptotic cell death that primarily involves iron overload, lipid peroxidation, and suppression of antioxidant systems. Increasing evidence indicates that ferroptosis plays an important role in viral infections. In this study, we show that PRV induces ferroptosis by disrupting iron homeostasis through TfR1 activation and ferritinophagy induction. On one hand, PRV infection upregulates TfR1 expression through HIF-1β and facilitates TfR1 translocation to the cell membrane via Rab11a, leading to enhanced import of extracellular Fe3+ into cells. On the other hand, PRV exploits the selective autophagy receptors NCOA4 and TAX1BP1, which strengthens the interaction between NCOA4, TAX1BP1, and FTH1, triggering ferritinophagy and increasing intracellular Fe2+ levels. Collectively, these findings enrich the understanding of the mechanism by which PRV induces ferroptosis, shedding new light on PRV and other alpha-herpesvirus infections.

Keywords:  PRV; TfR1; ferritinophagy; ferroptosis; iron homeostasis; programmed cell death

DOI:  https://doi.org/10.1128/jvi.00974-25
Plant Physiol Biochem. 2025 Aug 21. pii: S0981-9428(25)00946-5. [Epub ahead of print] 110418

Babaco mosaic virus BabMV induces defense metabolite production in papaya plants (Carica papaya).

Maria Gabriela Maridueña-Zavala, Carlos Noceda, Mohammed K Okla, Juan Manuel Cevallos-Cevallos, Gerrit T S Beemster, Hamada AbdElgawad.

  While the physiological and molecular responses of plants to viral infections are well documented, the progressive metabolic changes at different stages of the infection and their functional implications are still poorly understood. Therefore, this study investigates the dynamics of metabolic changes in papaya plants infected with Babaco Mosaic Virus (BabMV). We inoculated papaya plants with BabMV and collected leaf samples at 2, 10, 15, and 30 days post-inoculation (dpi). A PCA analysis revealed a separation of metabolic profiles of the infection stages. Early metabolic responses to stress (primarily at 2-10 dpi) could be associated with the accumulation of sulfur-containing amino acids and phenolic compounds. As the response progresses, at late stages (15-30dpi) metabolic shifts toward stress-defense metabolites occur, particularly involving proline and polyamine biosynthetic pathway and their precursors, including glutamine, ornithine, and arginine. Upregulation of key biosynthetic enzymes e.g., glutamine synthetase and pyrroline-5-carboxylate synthase for proline synthesis, and ornithine decarboxylase and spermidine synthase for polyamine production, coupled with downregulation of catabolic enzymes such as proline dehydrogenase and polyamine oxidase. There was a notable rise in phenylalanine levels alongside increased phenylalanine ammonia-lyase (PAL) activity, providing an explanation for the observed increase of phenolics and flavonoids levels. This metabolic shift likely contributes to the accumulation of antioxidant metabolites crucial for the plant's defense response.

Keywords:  Amino acids; BabMV; Phenolics compounds; Primary metabolism; Secondary metabolites; Virus infection

DOI:  https://doi.org/10.1016/j.plaphy.2025.110418
Metabolomics. 2025 Aug 29. 21(5): 127

Decoding blood fatty acids in Crimean-Congo hemorrhagic fever.

Serkan Bolat, Seyit Ali Büyüktuna, Serra İlayda Yerlitaş, Hayrettin Yavuz, Gözde Ertürk Zararsız, Meltem Kurt Yenihan, Merve Gülşah Lafçı, Ertuğrul Keskin, Yasemin Çakır Kıymaz, Gökmen Zararsız, Halef Okan Doğan.

   INTRODUCTION: Fatty acids (FAs) are essential for cellular structure, metabolism, and inflammatory regulation. This study investigated FA profiles in Crimean-Congo hemorrhagic fever (CCHF), a severe viral illness with high mortality rates, to explore their potential as disease progression and severity biomarkers.
METHODS: 190 participants were included in the study, comprising 115 CCHF-positive patients, 30 CCHF-negative patients, and 45 healthy controls. FA concentrations were analyzed via gas chromatography‒mass spectrometry (GC-MS).
RESULTS: Statistically significant differences in specific FA levels were observed between the study groups. Compared with mild and moderate cases, severe cases showed distinctive FA profiles. Notably, higher omega-6/omega-3 ratios and linoleic acid to dihomo-γ-linolenic acid (LA/DGLA) ratios are associated with severe disease outcomes and poor prognosis and are correlated with inflammatory markers such as IL-6 and D-dimer. Pathway analysis was performed to identify disruptions in fatty acid biosynthesis and metabolism. Additionally, Cox regression analyses were conducted to determine key fatty acids associated with prognosis. Regression analyses identified several key fatty acids influencing prognosis, including myristic acid, phytanic acid, linoleic acid, gamma-linolenic acid, alpha-linolenic acid, oleic acid, behenic acid, cerotic acid, linoleic acid DGLA, omega-6 fatty acids, omega-9 fatty acids, and the omega-6/omega-3 ratio. Pathway analysis revealed that the disruptions in the most affected pathways were the biosynthesis of unsaturated fatty acids, α-linolenic acid metabolism, elongation, degradation, arachidonic acid metabolism, and fatty acid biosynthesis in CCHF pathogenesis.
CONCLUSION: This study highlights significant alterations in fatty acid metabolism and laboratory markers in CCHF. These findings provide insights into the pathophysiology of this disease and may guide future research on targeted therapeutic strategies.

Keywords:  Crimean-Congo hemorrhagic fever; Disease severity; Fatty acid metabolism; Gas chromatography-mass spectrometry; Omega-3 fatty acids; Omega-6 fatty acids

DOI:  https://doi.org/10.1007/s11306-025-02327-y
Biology (Basel). 2025 Jul 25. pii: 938. [Epub ahead of print]14(8):

Comprehensive Analysis of Liver Transcriptome and Metabolome Response to Oncogenic Marek's Disease Virus Infection in Wenchang Chickens.

Lifeng Zhi, Xiangdong Xu, Yang Zeng, Wenquan Qin, Ganghua Li, Junming Zhao, Runfeng Zhang, Guang Rong.

  Marek's disease (MD), induced by the highly contagious Marek's disease virus (MDV), remains a significant challenge to global poultry health despite extensive vaccination efforts. This study employed integrated transcriptomic and metabolomic analyses to investigate liver responses in naturally MDV-infected Wenchang chickens during late infection stages. RNA sequencing identified 959 differentially expressed genes (DEGs) between the infected and uninfected groups. Functional enrichment analysis demonstrated that these DEGs were primarily associated with canonical pathways related to metabolism and cellular processes, including lipid, carbohydrate, and amino acid metabolism, as well as the p53 signaling pathway, cell cycle, and apoptosis. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) detected 561 differentially expressed metabolites (DEMs), showing near-significant enrichment (p = 0.069) in phenylalanine metabolism. Integrated analysis of transcriptomics and metabolomics data highlighted that critical gene-metabolite pairs such as SGPL1-palmitaldehyde-sphinganine-1-phosphate and ME1-NADP+-malic acid potentially mediate functional crosstalk between sphingolipid metabolism and cellular redox homeostasis during viral oncogenesis. This comprehensive mapping of regulatory networks provides insights into host-virus interactions during MDV pathogenesis, offering potential applications in immunomodulation approaches, targeted therapeutic strategies, and vaccine adjuvant development.

Keywords:  Marek’s disease virus; chicken; host response; metabolomics; transcriptomics

DOI:  https://doi.org/10.3390/biology14080938
Microb Pathog. 2025 Sep 01. pii: S0882-4010(25)00740-5. [Epub ahead of print] 108015

Comparative profiling of splenic phospholipid and sphingolipid during acute infection.

Tao Liu, Hong Jia, Hui Dong, Chaofei Cheng, Tao Zhang, Xinghui Zhao, Zhanzhong Zhao.

  Lipid profile of spleen and bursa of Fabricius (BF) during acute infection remains unknown. Acute infection models of porcine reproductive and respiratory syndrome virus (PRRSV), porcine epidemic diarrhea virus (PEDV) and Eimeria tenella (ET) were developed, and spleen samples with African swine fever virus (ASFV) or not were collected. Spleen and BF were examined and characteristic microscopic lesions were observed. Samples were analyzed using a semi-quantitative, untargeted method based on liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS-MS). After statistical analysis, potential biomarkers for PRRSV [16:0 20:5 phosphatidylcholine (16:0 20:5 PC), 18:1 lysophosphatidylcholine (18:1 LPC)], for PEDV [16:0 20:4 phosphatidylinositol (16:0 20:4 PI), 18:0 18:2 phosphatidylserine (18:0 18:2 PS), 16:0 lysophosphatidylserine (16:0 LysoPS), 18:0 LysoPS, d18:1 16:0 sphingomyelin (d18:1 16:0 SM)], for ASFV [16:0 18:0 PC, 16:0 20:4 PC, 18:0 20:4 PC, O-16:0 20:4 PC, O-18:1 20:4 PC, 16:0 18:2 phosphatidylethanolamine (16:0 18:2 PE), 16:0 18:1 PE, 18:0 20:4 PE, 16:0 18:2 PI, 18:0 18:1 PS], for ET with spleen [16:0 20:3 PC, 18:0 18:2 PC, 18:0 18:1 PI, 18:0 20:4 PI, 18:0 22:6 PI, d18:1 16:0 SM, d18:1 22:1 SM], for ET with BF [16:0 18:2 PI, 16:0 18:1 PI, 18:0 18:2 PI, 18:0 20:4 PI, 16:0 18:2 PS, 16:0 18:1 PS, 18:0 18:2 PS, 18:0 20:4 PS, 18:0 22:6 PS, 18:0 LysoPS, 20:4 arachidonic acid (20:4 AA), 22:6 docosahexaenoic acid (22:6 DHA)] were analyzed. Overall, lipid profiling of spleen and BF was demonstrated, contributing to understand the lipid biology of lymphoid organs and intervene acute infection.

Keywords:  Acute infection; LC-MS-MS; Phospholipid; Sphingolipid; Spleen; bursa of Fabricius

DOI:  https://doi.org/10.1016/j.micpath.2025.108015
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2511911122

Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape.

Enkai Li, Ruochen Zang, Takahiro Kawagishi, Wei Zhang, Kruthika Iyer, Gaopeng Hou, Qiru Zeng, Rita M Meganck, Susan R Ross, Xin Wang, Xiong Su, Siyuan Ding.

  Despite the clinical significance of many nonenveloped viruses, the molecular mechanisms of their internalization and membrane penetration are not well understood. Rotaviruses (RVs) are nonenveloped double-stranded RNA viruses and the leading cause of severe dehydrating diarrhea in infants and young children. We identified fatty acid 2-hydroxylase (encoded by FA2H) in the fatty acid 2-hydroxylation pathway as a proviral gene that supports RV infection. Genetic ablation of FA2H interfered with an early step in RV entry for multiple human and animal strains. Intestinal epithelial cell-specific deletion of Fa2h limited RV replication and diarrhea incidence in vivo. Using transmission electron microscopy and immunofluorescence, we found that viral particles were trapped in early and late endosomes in FA2H knockout cells, preventing their further exit into the cytosol. The defect in RV infectivity could be partially restored by treatment of cells with long-chain 2-hydroxy ceramides or a calcium channel activator that promotes Ca2+ efflux from endosomes. Both Junín virus, an arenavirus, and Shiga toxin, dependent on endosomal Ca2+ transport, required FA2H for efficient entry. Together, this study highlights a role of fatty acid 2-hydroxylation in RV entry into host cells and implicates 2-hydroxy ceramides as potential key regulators of endosomal Ca2+ levels, offering important insights for the development of host-directed therapies targeting fatty acid 2-hydroxylation to control microbial infections.

Keywords:  FA2H; calcium; endosome; rotavirus; uncoating

DOI:  https://doi.org/10.1073/pnas.2511911122
PLoS Pathog. 2025 Sep;21(9): e1013441

Glycosylphosphatidylinositol biosynthesis functions as a conserved host defense pathway against coronaviruses via regulation of LY6E.

Yanlong Ma, Fei Feng, Hui Feng, Xue Ma, Ziqiao Wang, Yutong Han, Yunkai Zhu, Yuyan Wang, Zhichao Gao, Yuyuan Zhang, Qiang Ding, Jincun Zhao, Rong Zhang.

Coronaviruses, including SARS-CoV-2, rely on host factors for their replication and pathogenesis, while hosts deploy defense mechanisms to counteract viral infections. Although numerous host proviral factors have been identified, the landscape of host restriction factors and their underlying mechanisms remain less explored. Here, we conducted genome-wide CRISPR knockout screens using three distinct coronaviruses-SARS-CoV-2, HCoV-OC43 (a common cold human virus from the genus Betacoronavirus) and porcine epidemic diarrhea virus (Alphacoronavirus) to identify conserved host restriction factors. We identified glycosylphosphatidylinositol (GPI) biosynthesis as the pan-coronavirus host factor that restrict viral entry by disrupting spike protein-mediated membrane fusion at both endosomal and plasma membranes. GPI biosynthesis generates GPI moieties that covalently anchor proteins (GPI-anchored proteins [GPI-APs]) to the cell membrane, playing essential roles in various cellular processes. Through focused CRISPR knockout screens targeting 193 GPI-APs, we identified LY6E, a known pan-coronavirus restriction factor for viral entry, as the key downstream effector mediating the antiviral activity of the GPI biosynthesis pathway. These findings reveal the role for GPI biosynthesis as a conserved host defense mechanism against coronaviruses via regulation of downstream effectors.

DOI: https://doi.org/10.1371/journal.ppat.1013441
Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2512385122

ARRDC4-mediated glycolysis enhances innate immunity to influenza A virus through fructose-1,6-bisphosphate.

Yuhan Li, Zhen Wang, Jie Wang, Zhimin Jiang, Mingyue Chen, Hui Ai, Chao Ma, Qi Tong, Litao Liu, Tony Velkov, Honglei Sun, Juan Pu, Jinhua Liu, Chongshan Dai, Yipeng Sun.

  Glucose metabolism impacts the innate immune response against viral infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we found that arrestin domain containing 4 (ARRDC4), a critical regulator of glucose metabolism, senses influenza A virus (IAV) infection by interacting with viral PA protein. Upregulated ARRDC4 increases the enzymatic activity of phosphofructokinase, muscle type (PFKM) via binding its His298 site to promote the production of the metabolite fructose-1,6-bisphosphate (FBP). Consequently, FBP inhibits the K48-linked ubiquitination degradation of HSP90β, subsequently enhances its interaction with IKKβ and IKKε, and enhances NF-κB- and IRF7-mediated antiviral innate immunity, respectively. Importantly, FBP supplementation enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Our findings highlight a unique immunometabolic regulatory mechanism in which ARRDC4 senses IAV infection and regulates antiviral innate immunity through the PFKM-FBP metabolic axis and provide a strategy for manipulating FBP-related metabolism to treat viral infection.

Keywords:  ARRDC4; fructose-1,6-bisphosphate; influenza; innate immunity; viral replication

DOI:  https://doi.org/10.1073/pnas.2512385122