bims-mevinf 2025-11-02 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–11–02
eleven papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

p53-mediated regulation of electron transport chain and nucleotide synthesis during Newcastle disease virus infection.
African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.
Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.
Porcine deltacoronavirus infection triggers mitophagy to dampen the interferon response and promote viral replication.
Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses.
Retinol binding protein 4 enhances cellular cholesterol uptake to facilitate influenza A virus infection.
Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication.
Activation of IRE1 Endonuclease Activity Regulates Zika Virus Replication and Antiviral Response During Infection in Human Microglia.
Preclinical Evaluation of the Efficacy of α-Difluoromethylornithine and Sulindac Against SARS-CoV-2 Infection.
Role of Unfolded Protein Response in the Apoptosis Induced by Alphaarterivirus: IRE1α as an Essential Pathway for In Vitro Replication.
ROS-Mediated Necroptosis Promotes Coxsackievirus B3 Replication and Myocardial Injury.

J Virol. 2025 Oct 31. e0157625

p53-mediated regulation of electron transport chain and nucleotide synthesis during Newcastle disease virus infection.

Changrun Zhao, Ning Tang, Jing Wang, Yang Qu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Tingrong Luo, Chan Ding, Yingjie Sun.

  Mitochondria and their electron transport chain (ETC) constitute the central machinery for cellular energy metabolism and biosynthetic regulation. Disruption of the ETC leads to reactive oxygen species (ROS) production and metabolic imbalance, but its precise role in viral replication and infection remains to be elucidated. In this study, we used Newcastle disease virus (NDV), an important avian pathogen and a promising oncolytic virus, as a model to explore its relationship with cellular mitochondrial metabolism. We demonstrate that NDV infection induces varying degrees of mitochondrial fragmentation, membrane potential dissipation, and ROS production, especially in p53-null H1299 cells compared to p53-wild-type A549 cells. ETC impairment restricts NDV replication primarily by limiting aspartate and pyrimidine nucleotide biosynthesis, rather than through ROS-mediated cytotoxicity or energy depletion. Notably, NDV replication in p53-null cells is highly sensitive to ETC complexes I and III inhibition, which can be rescued by exogenous aspartate or uridine supplementation. Mechanistically, p53 serves as a metabolic buffer, protecting mitochondrial function and maintaining precursor availability during viral infection. These findings elucidate the selective and differential utilization of mitochondrial ETC components by NDV and reveal that p53 status shapes cellular susceptibility to NDV-induced metabolic stress. Our work highlights mitochondrial metabolism and p53 as potential targets for antiviral and oncolytic strategies against NDV.IMPORTANCEThis study uncovers the intricate relationship between Newcastle disease virus (NDV) infection and host cell mitochondrial metabolism, with a particular emphasis on the pivotal regulatory role of p53. As both an important avian pathogen and a promising oncolytic virus, NDV disrupts mitochondrial function and the electron transport chain, leading to p53-mediated alterations in cellular energy metabolism and redox homeostasis. Our findings not only deepen the understanding of NDV-mitochondria interactions but also highlight the central role of p53 in viral infection and oncolytic mechanisms. These insights provide a theoretical foundation and novel therapeutic targets for antiviral and anticancer strategies based on p53 or mitochondrial pathways.

Keywords:  NDV; electron transport chain; mitochondrial metabolism; nucleotide synthesis; p53; reactive oxygen species

DOI:  https://doi.org/10.1128/jvi.01576-25
J Virol. 2025 Oct 31. e0098525

African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.

Zebu Song, Yilin Chen, Hui Guo, Guihong Zhang, Lang Gong, Zezhong Zheng.

  African swine fever (ASF) is a highly contagious disease of pigs caused by the African swine fever virus (ASFV), posing a significant threat to global swine production. As an obligate intracellular parasite, ASFV relies on host metabolic networks to fulfill its replication requirements. However, the precise mechanisms by which it manipulates nucleotide metabolism remain unclear. In this study, untargeted metabolomic analysis of ASFV-infected porcine alveolar macrophages revealed significant perturbations in purine and pyrimidine metabolism, glycolysis, the pentose phosphate pathway (PPP), and the glutamate and aspartate metabolic pathways. Functional validation demonstrated that ASFV depends on de novo pyrimidine biosynthesis for viral genome replication. Notably, ASFV employs a dual strategy to sustain the supply of nucleotide precursors: (i) it hijacks the PPP to generate ribose-5-phosphate and NADPH for redox balance, and (ii) it enhances glutamine uptake and catabolism to provide the nitrogen and carbon needed for nucleotide biosynthesis and tricarboxylic acid cycle replenishment. Furthermore, although aspartate is essential for pyrimidine synthesis, ASFV circumvents dependence on extracellular aspartate by activating a cytosolic GOT1-mediated synthesis pathway. Collectively, these findings elucidate how ASFV reprograms host nucleotide metabolism to support its replication, offering new insights into virus-host metabolic interactions and identifying potential targets for antiviral therapy.IMPORTANCEAfrican swine fever (ASF) is a devastating disease that causes substantial economic losses in the global pig industry. This study demonstrates that the African swine fever virus (ASFV) reprograms host cell metabolism to produce the essential building blocks required for its replication. Specifically, ASFV manipulates host nucleotide biosynthetic pathways to secure both the substrates for DNA synthesis and the reducing power necessary to mitigate oxidative stress. Elucidating these metabolic interactions not only deepens understanding of ASFV pathogenesis but also highlights promising metabolic targets for antiviral therapy. By elucidating how ASFV hijacks nucleotide biosynthesis within infected cells, our findings pave the way for innovative strategies to combat ASF.

Keywords:  African swine fever virus; aspartate; glutamine; metabolic hijacking; pyrimidine metabolism

DOI:  https://doi.org/10.1128/jvi.00985-25
Viruses. 2025 Oct 17. pii: 1386. [Epub ahead of print]17(10):

Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.

Xianfeng Hui, Xiaowei Tian, Shihuan Ding, Ge Gao, Xin Zhao, Jiyan Cui, Yiru Hou, Tiesuo Zhao, Hui Wang.

  Influenza viruses are adept at hijacking host cellular machinery to facilitate their replication and propagation. A critical aspect of this hijacking involves the reprogramming of host cell metabolism. This review summarizes current findings on how influenza virus infection alters major metabolic pathways, including enhanced glycolysis, suppression of oxidative phosphorylation, diversion of TCA cycle intermediates for biosynthesis, and upregulation of lipid and amino acid metabolism. Key nutrients like glucose, glutamine, and serine are redirected to support viral RNA synthesis, protein production, and membrane formation. Moreover, these metabolic changes also modulate host immune responses, potentially aiding in immune evasion. We highlight the role of transcription factors such as SREBPs in lipid synthesis and the impact of one-carbon metabolism on epigenetic regulation. Finally, we discuss how targeting virus-induced metabolic shifts, using agents like 2-deoxyglucose or fatty acid synthesis inhibitors, offers promising avenues for antiviral intervention, while emphasizing the need for selective approaches to minimize harm to normal cells.

Keywords:  amino acid metabolism; antiviral strategies; cellular metabolism; glycolysis; influenza virus; lipid biosynthesis

DOI:  https://doi.org/10.3390/v17101386
Front Immunol. 2025 ;16 1684178

Porcine deltacoronavirus infection triggers mitophagy to dampen the interferon response and promote viral replication.

Yue Chen, Yuan Zhao, Qingqing Song, Shijing Zhang, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Xiangdong Li.

  Porcine deltacoronavirus (PDCoV) is a newly emerging enteric pathogenic that causes severe diarrhea in neonatal piglets worldwide and presents a significant public health threat due to its potential for cross-species transmission. MAVS (Mitochondrial Antiviral Signaling Protein), serves as a crucial immune hub that connects virus recognition (RIG-I/MDA5) and interferon response. In this study, we found that PDCoV infection damage mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization and reduction in mitochondrial numbers. In addition, PDCoV infection triggered mitophagy to eliminate the impaired mitochondria and degradation of MAVS, which resulted in a suppression of Interferon type I (IFN-I) production, thereby promoting viral replication. In conclusion, the data of this study indicate that PDCoV can degrade MAVS through mitophagy to weak the production of IFN-I, thereby promoting virus replication.

Keywords:  MAVS; interferons production inhibition; mitochondrial damage; mitophagy; porcine deltacoronavirus (PDCoV)

DOI:  https://doi.org/10.3389/fimmu.2025.1684178
Int J Mol Sci. 2025 Oct 10. pii: 9853. [Epub ahead of print]26(20):

Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses.

Paula Martínez de Iturrate, Bruno Hernáez, Patricia de Los Santos, Yolanda Sierra-Palomares, Alba García-Gómez, Alonso Sánchez-Cruz, Catalina Hernández-Sánchez, Luis Rivas, Margarita Del Val, Eduardo Rial.

  Respiratory viral infections are a major cause of morbidity and mortality worldwide. The COVID-19 pandemic has evidenced the need for broad-spectrum antivirals and improved preclinical models that more accurately recapitulate human respiratory disease. These new strategies should also involve the search for drug targets in the infected cell that hamper the development of resistance and of potential efficacy against diverse viruses. Since many viruses reprogram cellular metabolism to support viral replication, we performed a comparative analysis of inhibitors targeting the PI3K/AKT/mTOR pathway, central to virus-induced metabolic adaptations, using MRC5 lung fibroblasts and Huh7 hepatoma cells. HCoV-229E infection in MRC5 cells caused the expected shift in the energy metabolism but the inhibitors had markedly different effects on the metabolic profile and antiviral activity in these two cell lines. Dichloroacetate (DCA), a clinically approved inhibitor of aerobic glycolysis, showed antiviral activity against HCoV-229E in MRC5 cells, but not in Huh7 cells, underscoring that the screening model is more critical than previously assumed. We further tested DCA in polarized human small airway epithelial cells cultured in air-liquid interface, a 3D model that mimics the human respiratory tract. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2, and respiratory syncytial virus by 2-3 orders of magnitude, even when administered after infection was established. Our work reinforces the need for advanced human preclinical screening models to identify antivirals that target host metabolic pathways frequently hijacked by respiratory viruses, and establishes DCA as a proof-of-concept candidate.

Keywords:  antiviral; coronavirus; dichloroacetate; energy metabolism; respiratory infection; respiratory syncytial virus; small airway epithelia

DOI:  https://doi.org/10.3390/ijms26209853
PLoS Pathog. 2025 Oct;21(10): e1013623

Retinol binding protein 4 enhances cellular cholesterol uptake to facilitate influenza A virus infection.

Hejiao Zhao, Yalu Zhang, Qingbing Han, Huanan Li, Wenjun Liu, Lei Sun, Yingli Shang.

Viruses hijack host cell machinery to facilitate their own replication. Therefore, identifying key cellular factors and processes involved in viral infection is crucial for developing host-directed therapies. Herein, we demonstrate that retinol-binding protein 4 (RBP4), a lipocalin family member and major retinol carrier, is significantly induced by influenza A virus (IAV) infection in both cellular models and clinical patients. Moreover, RBP4 deficiency impairs IAV replication both in vitro and in vivo. Mechanistically, RBP4 promotes the expression of CD36, a cholesterol uptake receptor protein, thereby increasing cellular cholesterol levels. This elevation in cholesterol subsequently boosts cell-surface sialic acid levels, facilitating IAV attachment. Consequently, enforced expression of CD36 restores IAV replication in RBP4-deficient cells and mice. In summary, our study identifies RBP4 as a pivotal host factor that facilitates IAV infection by modulating cellular cholesterol homeostasis.

DOI: https://doi.org/10.1371/journal.ppat.1013623
Adv Sci (Weinh). 2025 Oct 27. e09148

Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication.

Pengjun Wei, Zongzheng Zhao, Ruoqi Xu, Qin Yan, Liangzi Jiang, Fuxiao Geng, Yang Gu, Tianjiao Wang, Jing Zhou, Xiao Li, Qin Yan, Chun Lu, Wan Li.

  The global outbreak of mpox caused by the mpox virus (MPXV) in 2022 and 2024 underscores the urgent need to elucidate mechanisms governing viral replication during pathogenesis. Metabolic reprogramming is a conserved hallmark of viral infections, however, the precise mechanisms by which MPXV manipulates host cell metabolism remain unknown. Here, it is demonstrated that MPXV hijacks aerobic glycolysis via lysine crotonylation of its I3 protein, which is essential for MPXV replication. Mechanistically, MYST histone acetyltransferase 1 (MYST1), an acetyltransferase upregulated by MPXV, binds to and catalyzes the crotonylation of I3. The crotonylated I3 interacts with WD-repeat protein 26 (WDR26) to prevent its ubiquitination-dependent degradation, leading to enhanced aerobic glycolysis and promoting MPXV replication. Either pharmacological inhibition of MYST1 using MC4033 or blocking aerobic glycolysis with the glycolytic inhibitors 2-Deoxy-D-glucose (2-DG) or dichloroacetic acid (DCA) effectively suppresses MPXV replication. These findings uncover a novel crotonylation-dependent mechanism through which MPXV reprograms host metabolism to facilitate viral propagation, and identify lysine crotonylation and aerobic glycolysis as potential therapeutic targets against mpox.

Keywords:  I3; MYST1; aerobic glycolysis; crotonylation; mpox virus

DOI:  https://doi.org/10.1002/advs.202509148
Viruses. 2025 Sep 24. pii: 1291. [Epub ahead of print]17(10):

Activation of IRE1 Endonuclease Activity Regulates Zika Virus Replication and Antiviral Response During Infection in Human Microglia.

Tomás Hernández-Díaz, Aarón Oyarzún-Arrau, Aracelly Gaete-Argel, Delia López-Palma, Javier López-Schettini, Dominique Fernández, Fernando Valiente-Echeverría, Fabiola Osorio, Ricardo Soto-Rifo.

  Zika virus (ZIKV) can infect and replicate in the endoplasmic reticulum (ER) of different human cell types, including neural progenitor cells, radial glial cells, astrocytes, and microglia in the brain. ZIKV infection of microglia is expected to trigger both ER stress and the induction of an antiviral response through production of type-I interferons and pro-inflammatory cytokines, contributing to neuroinflammation during infection. Despite their critical role in ZIKV pathogenesis, the interplay between ER stress and the antiviral response during infection has not been fully characterized in human microglia. In this work, we show that infection of a human microglia cell line with ZIKV triggers the induction of an antiviral response and the activation of the endonuclease activity of the unfolded protein response sensor IRE1. Interestingly, we observed that both IRE1 and XBP1 were sequestered to the viral replication sites during infection. Moreover, pharmacological inhibition or hyperactivation of the endonuclease activity of IRE1 resulted in reduced viral titers. As such, while inhibition of IRE1 resulted in an increased type-I interferon response, hyperactivation led to a decrease in ZIKV RNA levels and the appearance of ER-derived cytoplasmic structures containing NS3, IRE1, and XBP1. Together, our data indicate that regulation of the endonuclease activity of IRE1 is critical for both ZIKV replication and immune activation, highlighting the potential of the ER stress sensor as a target for the development of antivirals to treat ZIKV infections.

Keywords:  ER stress; IRE1; Zika virus; innate immune response; microglia

DOI:  https://doi.org/10.3390/v17101291
Viruses. 2025 Sep 26. pii: 1306. [Epub ahead of print]17(10):

Preclinical Evaluation of the Efficacy of α-Difluoromethylornithine and Sulindac Against SARS-CoV-2 Infection.

Natalia A Ignatenko, Hien T Trinh, April M Wagner, Eugene W Gerner, Christian Bime, Chiu-Hsieh Hsu, David G Besselsen.

  Despite numerous research efforts and several effective vaccines and therapies developed against coronavirus disease 2019 (COVID-19), drug repurposing remains an attractive alternative approach for treatment of SARS-CoV-2 variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of two polyamine metabolism-targeting drugs, an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), and a non-steroidal anti-inflammatory drug (NSAID), Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in the human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. In the infected human cell lines, the DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The Sulindac alone and DFMO/Sulindac combination treatments also suppressed the expression of the viral Spike protein and the host angiotensin-converting enzyme 2 (ACE2). In K18-hACE2 mice, the antiviral activity of DFMO and Sulindac as single agents and in combination was tested as prophylaxis (drug supplementation started 7 days before infection) or as treatment (drug supplementation started 24 h post-infection) at the doses equivalent to patient chemoprevention trials (835 ppm DFMO and 167 ppm Sulindac). The drugs' antiviral activity in vivo was evaluated by measuring the clinical (survival rates and clinical scores), viral (viral load and virus infectivity), and biochemical (plasma polyamine, Sulindac, and Sulindac metabolite levels) endpoints. Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p = 0.01 and p = 0.027, respectively), and the combination was effective in the aged male mice (p = 0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p = 0.001) and the DFMO/Sulindac combination (p = 0.018), while aged female mice did not benefit significantly from any intervention. Treatment of SARS-CoV-2-infected animals with DFMO or/and Sulindac did not significantly improve their survival rates. Overall, our studies demonstrated that DFMO and Sulindac administration as the prophylaxis regimen provided strong protection against the lethal outcome of SARS-CoV-2 infection and that male mice benefited more from the polyamine-targeted antiviral treatment than female mice. Our findings underscore the importance of evaluation of the antiviral activity of the drugs in the context of sex and age.

Keywords:  COVID-19 mouse model; DFMO; SARS-CoV-2; Sulindac; antiviral drugs; polyamines

DOI:  https://doi.org/10.3390/v17101306
Viruses. 2025 Sep 25. pii: 1301. [Epub ahead of print]17(10):

Role of Unfolded Protein Response in the Apoptosis Induced by Alphaarterivirus: IRE1α as an Essential Pathway for In Vitro Replication.

Santiago Emanuel Colina, Macarena Marta Williman, María Soledad Serena, María Gabriela Echeverría, Germán Ernesto Metz.

  The perturbation of ER homeostasis by viral infection gives rise to the unfolded protein response (UPR), characterized by the activation of three signaling pathways. PERK, IRE1, and ATF6 have been identified as the primary mediators responsible for restoring homeostasis or leading to apoptosis in response to stress. Alphaarterivirus equid, known as equine arteritis virus (EAV), is a RNA virus with importance in the equine industry that could persist in semen and lead to abortions in pregnant mares. The present article explores the consequences of in vitro infection with the EAV Bucyrus strain on UPR. Employing RT-PCR, qPCR and Western blot, our investigation has revealed the activation of PERK and IRE1α pathways, whilst ATF6 has been suppressed. Furthermore, the p38α MAPK, caspase-12, and CHOP genes were found to be upregulated, demonstrating the induction of apoptosis. Finally, in the inhibition experiments, the PERK pathway was found to be implicated in the modulation of viral replication in the initial phases of infection. Conversely, the IRE1α pathway was identified as the predominant UPR pathway in EAV replication, as evidenced by the complete inhibition of replication observed in these experiments. Consequently, the further exploration of this UPR pathway is necessary to determine whether it can effectively suppress EAV replication.

Keywords:  ER stress; IRE1α; PERK; RNA virus; apoptosis; equine arteritis virus

DOI:  https://doi.org/10.3390/v17101301
Microorganisms. 2025 Oct 17. pii: 2389. [Epub ahead of print]13(10):

ROS-Mediated Necroptosis Promotes Coxsackievirus B3 Replication and Myocardial Injury.

Junbo Huang, Yanjun Di, Qing Song, Zhiyun Cheng, Hao Wu, Mei Wu, Minjian He, Genrui Zhang, Fucai Wang, Lei Tong.

  Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis (VMC), which can lead to both acute and chronic cardiac inflammation accompanied by progressive heart failure and arrhythmias. Although CVB3 has been implicated in various forms of programmed cell death, whether it triggers necroptosis and the underlying mechanisms remains unclear. This study aimed to investigate the role and mechanism of CVB3-induced necroptosis and its effect on viral replication. Using both in vitro and in vivo models, we demonstrated that CVB3 infection significantly upregulates the expression of key necroptotic markers RIP1 and RIP3 in HeLa cells and mouse myocardial tissues. This upregulation was accompanied by elevated intracellular reactive oxygen species (ROS) levels and suppression of the Nrf2/HO-1 antioxidant pathway. Intervention with the necroptosis inhibitor Necrostatin-1 (Nec-1) or the ROS scavenger N-acetylcysteine (NAC) markedly attenuated cell death, suppressed viral replication, and ameliorated myocardial injury and inflammatory responses in infected mice. Mechanistically, CVB3 inhibits the Nrf2/HO-1 pathway, thereby inducing substantial ROS accumulation that promotes necroptosis. This effect can be reversed by NAC treatment. Our study reveals a novel mechanism through which CVB3 induces ROS-dependent necroptosis via the suppression of the Nrf2/HO-1 pathway, providing new insights into the pathogenesis of viral myocarditis and suggesting potential therapeutic strategies.

Keywords:  RIP1; RIP3; ROS; coxsackievirus B3; necroptosis; viral myocarditis

DOI:  https://doi.org/10.3390/microorganisms13102389