bims-mevinf 2025-06-01 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–06–01
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Infectious Spleen and Kidney Necrosis Virus Triggers Ferroptosis in CPB Cells to Enhance Virus Replication.
Respiratory Syncytial Virus Elicits Glycolytic Metabolism in Pediatric Upper and Lower Airways.
Suppression of Monkeypox Virus by Downregulation of Fatty Acid Synthase and Upregulation of Cholesterol-25 Hydroxylase.
PKM2 Facilitates Classical Swine Fever Virus Replication by Enhancing NS5B Polymerase Function.
Vitamin C Inhibits Scale Drop Disease Virus Infectivity by Targeting Nrf2 to Reduce Ferroptosis.
BTP2 restricts Tulane virus and human norovirus replication independent of store-operated calcium entry.
SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway.
Selenoprotein M Inhibits the Replication of Influenza A Virus by Regulating Reactive Oxygen Species Levels.
Tapping into Metabolomics for Understanding Host and Rotavirus Group A Interactome.

Viruses. 2025 May 16. pii: 713. [Epub ahead of print]17(5):

Infectious Spleen and Kidney Necrosis Virus Triggers Ferroptosis in CPB Cells to Enhance Virus Replication.

Qiushuang Zhang, Ouqin Chang, Qiang Lin, Hongru Liang, Yinjie Niu, Xia Luo, Baofu Ma, Ningqiu Li, Xiaozhe Fu.

  The role of ferroptosis-a novel iron-dependent programmed cell death pathway-in infectious spleen and kidney necrosis virus (ISKNV) infection remains poorly understood. Here, we demonstrate that ISKNV infection induces ferroptosis in CPB cells. Following ISKNV challenge, CPB cells exhibited hallmark morphological alterations including mitochondrial shrinkage, increased membrane density, and cristae reduction. Biochemical assays confirmed significant time-dependent elevations in ferroptosis markers: malondialdehyde (MDA, 1.7-fold), reactive oxygen species (ROS, 3.14-fold), and ferrous iron (Fe2+, 1.42-fold) compared to controls (p < 0.05). Mechanistic studies revealed that ISKNV downregulated glutathione peroxidase 4 (GPx4) while upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4), as validated by quantitative real-time PCR (qRT-PCR) and immunoblotting. Ferroptosis induction with erastin enhanced ISKNV replication, whereas inhibition with liproxstatin-1 suppressed viral yield. These findings establish that ISKNV exploits ferroptosis to facilitate its replication, and pharmacological blockade of this pathway significantly suppresses viral propagation, providing a new strategy and intervention approach for controlling ISKNV infection.

Keywords:  ACSL4; GPx4; ISKNV; ferroptosis; viral replication

DOI:  https://doi.org/10.3390/v17050713
Viruses. 2025 May 14. pii: 703. [Epub ahead of print]17(5):

Respiratory Syncytial Virus Elicits Glycolytic Metabolism in Pediatric Upper and Lower Airways.

Armando S Flores-Torres, Svetlana Rezinciuc, Lavanya Bezavada, Barry L Shulkin, Stephania A Cormier, Heather S Smallwood.

  Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract viral infection in infants and causes around 60,000 in-hospital deaths annually. Emerging evidence suggests that RSV induces metabolic changes in host cells to support viral replication, presenting a potential target for therapeutic intervention. To investigate RSV-driven metabolic changes in situ, we combined positron emission tomography (PET), live-cell bioenergetics, and metabolomic profiling in the upper and lower airways of children. PET imaging revealed persistent, hyper-glycolytic regions in the lungs of RSV-infected children. Bioenergetic analysis of freshly collected nasopharyngeal aspirates from infants showed live upper respiratory cells (URCs) infected with RSV in situ exhibited significantly higher levels of glycolysis, glycolytic capacity, glycolytic reserves, and mitochondrial respiration than uninfected controls. Metabolomic analysis of nasopharyngeal fluids from these patients revealed distinct metabolic signatures, including increased citrate and malate, and decreases in taurine. In vitro infection of pediatric nasopharynx tissue-derived multicellular epithelial cultures (TEpiCs) and bronchial epithelial cells further confirmed RSV-induced increases in glycolysis. Together, these findings demonstrate that RSV infection induces hypermetabolism in both upper and lower primary airways in situ, supporting the potential of host-targeted metabolic interventions as a therapeutic strategy-particularly in vulnerable populations such as infants for whom vaccines are not currently available.

Keywords:  RSV; airway epithelial cells; bioenergetics; glycolysis; infant; metabolism; oxidative phosphorylation; pediatric; respiratory syncytial virus; viral infection

DOI:  https://doi.org/10.3390/v17050703
J Med Virol. 2025 Jun;97(6): e70403

Suppression of Monkeypox Virus by Downregulation of Fatty Acid Synthase and Upregulation of Cholesterol-25 Hydroxylase.

Saba R Aliyari, Jean Shanaa, Daniel Yu, Mari Yamamoto, Kaitlyn N Bateman, Lulan Wang, Michael E Jung, Genhong Cheng.

  The World Health Organization declared the spread of monkeypox virus (MPXV) across multiple African countries a public health emergency of international concern in August 2024. This marks the second such declaration in the past 2 years in response to the MPXV transmission. The re-emergence of the MPXV 3 years after the start of the SARS-CoV-2 epidemic further emphasizes the need to develop broad spectrum antivirals that might control the spread of poorly understood pathogens. The induction of innate immune responses to a viral infection triggers rapid expression of type-I-interferon, which subsequently leads to the differential regulation of over 300 genes that collectively establish an antiviral state. While most of these "interferon-stimulated genes" (ISGs) are upregulated, some are downregulated. Notably, the expression of certain ISGs involved in lipid metabolism is suppressed, which can be exploited by viruses to facilitate their replication. Herein, we report that the expression of fatty acid synthase (FASN), an enzyme involved in de novo biosynthesis of fatty acids, was significantly reduced upon MPXV infection. Moreover, MPXV infection was impaired in FASN knockout cells, and biological inhibitors of FASN significantly inhibited MPXV. Interestingly, chosterol-25-hydroxylase was induced in MPXV-infected cells, and its enzymatic product, 25-hydroxychlosterol (25HC), blocked MPXV infection. Overall, this study suggests that 25HC and FASN inhibitors exhibit significant antiviral activity and may have therapeutic applications in combating understudied infectious diseases in early outbreak settings when targeted therapies have not yet been developed.

Keywords:  25‐Hydroxycholesterol; Poxvirus; antiviral agents; fatty acid synthase; interferon

DOI:  https://doi.org/10.1002/jmv.70403
Viruses. 2025 Apr 29. pii: 648. [Epub ahead of print]17(5):

PKM2 Facilitates Classical Swine Fever Virus Replication by Enhancing NS5B Polymerase Function.

Mengzhao Song, Shanchuan Liu, Yan Luo, Tiantian Ji, Yanming Zhang, Wen Deng.

  Host metabolic reprogramming is a critical strategy employed by many viruses to support their replication, and the key metabolic enzyme plays important roles in virus infection. This study investigates the role of pyruvate kinase M2 (PKM2), a glycolytic enzyme with non-canonical functions, in the replication of classical swine fever virus (CSFV). Using PK-15 cells and piglet models, we demonstrate that CSFV infection upregulates PKM2 expression both in vitro and in vivo, creating a proviral environment. knockdown of PKM2 by siRNA reduced CSFV proliferation, while PKM2 overexpression significantly increased virus propagation, which was evaluated by viral protein synthesis, genome replication, and progeny virion production. A direct interaction between PKM2 and CSFV NS5B protein was identified by co-immunoprecipitation and GST-pulldown assays, and PKM2 affected NS5B polymerase activity in a dual-luciferase reporter assay, with PKM2 depletion reducing RdRp function by 50%. Temporal analysis of the first viral replication cycle confirmed PKM2-dependent enhancement of CSFV RNA synthesis. These findings establish PKM2 as a proviral host factor that directly binds NS5B to potentiate RdRp activity, thereby bridging metabolic adaptation and viral genome replication. This study provides new evidence of a glycolytic enzyme physically interacting and enhancing viral polymerase function, offering new information about CSFV-host interaction.

Keywords:  NS5B; RdRp activity; classical swine fever virus; pyruvate kinase M2; viral infection

DOI:  https://doi.org/10.3390/v17050648
Antioxidants (Basel). 2025 May 10. pii: 576. [Epub ahead of print]14(5):

Vitamin C Inhibits Scale Drop Disease Virus Infectivity by Targeting Nrf2 to Reduce Ferroptosis.

Jiaming Chen, Yuting Fu, Shaoping Weng, Jianguo He, Chuanfu Dong.

  Scale drop disease virus (SDDV) poses an escalating threat to global aquaculture, prompting an urgent need for research. Our study found that SDDV infection upregulates genes related to iron, oxidative stress, and lipid metabolism, causing iron overload, reactive oxygen species (ROS) accumulation, and ultimately ferroptosis. Among the tested antioxidants, vitamin C (VC) demonstrated the most potent inhibitory effect in mandarin fish, reducing SDDV-induced mortality by 37.5%. qPCR and IFA results showed that VC effectively suppressed SDDV infection; decreased ROS, lipid peroxidation (LPO), and iron levels; and enhanced glutathione peroxidase 4 (GPX4) expression in infected cells. Mechanistically, VC's inhibitory effect was reversed by the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML-385, indicating an Nrf2-dependent pathway. VC promoted Nrf2 nuclear translocation and activated downstream antioxidant genes. Moreover, VC modulated inflammation by regulating pro- and anti-inflammatory factors. These findings suggest VC as a promising therapeutic for SDDV infection.

Keywords:  Nrf2; antioxidant; ferroptosis; inflammation; scale drop disease virus; vitamin C

DOI:  https://doi.org/10.3390/antiox14050576
J Virol. 2025 May 29. e0044425

BTP2 restricts Tulane virus and human norovirus replication independent of store-operated calcium entry.

Francesca J Scribano, J Thomas Gebert, Kristen A Engevik, Nicole M Hayes, Jorge Villanueva, Son Pham, Soni Kaundal, Janam J Dave, B V Venkataram Prasad, Mary K Estes, Sasirekha Ramani, Joseph M Hyser.

  Human norovirus is the leading cause of viral gastroenteritis across all age groups. While there is a need for human norovirus antivirals, therapeutic development has been hindered by a lack of cell culture systems and animal models of infection. Surrogate viruses, such as Tulane virus (TV), have provided tractable systems to screen potential antiviral compounds. Our previous work demonstrated that TV encodes a viral ion channel, which dysregulates cytosolic calcium signaling. We set out to investigate whether host pathways triggered by viral ion channel activity, including store-operated calcium entry (SOCE), play a role in virus replication. Using pharmacologic inhibitors and genetically engineered cell lines, we establish that the SOCE inhibitor, BTP2, reduces TV replication in an SOCE-independent manner. We observed a significant reduction in TV replication, protein expression, and RNA synthesis in cells with both pre- and post-infection BTP2 treatment. By serial passage and plaque isolation, we demonstrate that TV quasi-species have mixed susceptibility and resistance to BTP2. Sequence comparison of the quasi-species revealed that amino acid changes in the structural proteins were associated with drug resistance. We utilized reverse genetics to generate TV with the resistance-associated VP1 and VP2 amino acid changes and found that amino acid changes in both proteins conferred BTP2 resistance. Together, this supports that TV structural proteins are the targets of BTP2. Finally, using human intestinal organoids, we demonstrate that BTP2 significantly reduces human norovirus replication.IMPORTANCEOur work identifies BTP2 as a potential human norovirus antiviral pharmacophore and highlights the utility of targeting calicivirus structural proteins to restrict viral replication. Furthermore, we establish a system whereby Tulane virus (TV) can be used to screen novel antiviral candidates and establish their mechanism of action. Together, this will facilitate rapid preclinical validation of other novel human norovirus therapeutics.

Keywords:  BTP2; Tulane virus; antiviral; human norovirus

DOI:  https://doi.org/10.1128/jvi.00444-25
mBio. 2025 May 28. e0042525

SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway.

Hua Yang, Pak-Hin Hinson Cheung, Li Wu.

  Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. While SAMHD1 is known to promote spontaneous apoptosis, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unclear. In this study, we identify a novel mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway. We demonstrate that SAMHD1 enhances apoptosis induced by HIV-1 infection in dividing monocytic THP-1 and U937 cell lines, but not in differentiated macrophage-like cells. Mechanistically, SAMHD1 expression reduces mitochondrial membrane potential and promotes cytochrome c release in HIV-1-infected THP-1 cells, thereby augmenting the mitochondrial apoptotic pathway. Furthermore, SAMHD1-enhanced apoptosis is linked to elevated levels of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells, which contributes to enhanced apoptosis during HIV-1 infection. These findings reveal a previously unrecognized regulatory role of SAMHD1 in amplifying HIV-1-induced apoptosis in monocytic cells, highlighting its involvement in the mitochondrial apoptotic pathway.IMPORTANCESterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, lowers intracellular dNTP levels and restricts HIV-1 replication in non-dividing cells. HIV-1 infection induces cell death mainly through apoptosis. While we have shown that endogenous SAMHD1 enhances spontaneous apoptosis in monocytic cells, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unknown. In this study, we aim to bridge this knowledge gap by investigating the functional significance of SAMHD1 in regulating apoptosis during HIV-1 infection of immune cells. Our findings reveal a novel mechanism whereby SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. This suggests a previously unrecognized role of SAMHD1 in modulating cellular responses to HIV-1 infection.

Keywords:  BCL-2-interacting killer; HIV-1 infection; SAMHD1; THP-1 cells; apoptosis; cytochrome c; mitochondrial membrane potential; mitochondrial pathway; monocytic cells

DOI:  https://doi.org/10.1128/mbio.00425-25
Life (Basel). 2025 Apr 28. pii: 714. [Epub ahead of print]15(5):

Selenoprotein M Inhibits the Replication of Influenza A Virus by Regulating Reactive Oxygen Species Levels.

Minxuan Liu, Jinhui Wang, Weigang Li, Bo Zhao, Yuanyuan Zhang, Guangyuan Liu, Qiaoying Zeng.

  Background: Influenza A virus (IAV) is the major pathogen responsible for influenza pandemics and can cause seasonal influenza outbreaks. In general, viral infection of host cells increases reactive oxygen species (ROS) levels, a process that triggers cell death, lung injury (LI), and other damage mechanisms. Methods: In our previous study, we revealed that selenoproteins may inhibit IAV replication at the cellular level. In this study, we determined the effect of selenoprotein M (SelM) on Nanoluc-IAV-PR8 replication through Nanoluc analysis. The mechanism through which selenoprotein inhibits the replication of the influenza virus was investigated using the SelM knockout cell line, nano-luciferase reporter assays, RNAi, qPCR, Western blot, and confocal microscopy. Results: Our experimental results show that SelM can effectively inhibit the replication of influenza A viruses and could potentially be used as a broad-spectrum inhibitor for IAV therapy in future clinical treatments. The increase in ROS levels induced by IAV infection was found to be inhibited by SelM, which possesses an important Sec functional site, thus weakening the ability of IAV to replicate in cells. Conclusions: The results of this study highlight SelM as a selenoprotein that can effectively inhibit IAV replication.

Keywords:  influenza A virus; inhibited replication; reactive oxygen species; selenocysteine site; selenoprotein M

DOI:  https://doi.org/10.3390/life15050714
Life (Basel). 2025 May 10. pii: 765. [Epub ahead of print]15(5):

Tapping into Metabolomics for Understanding Host and Rotavirus Group A Interactome.

Phiona Moloi Mametja, Mmei Cheryl Motshudi, Clarissa Marcelle Naidoo, Kebareng Rakau, Luyanda Mapaseka Seheri, Nqobile Monate Mkolo.

  Group A rotavirus continues to be a leading global etiological agent of severe gastroenteritis in young children under 5 years of age. The replication of this virus in the host is associated with the occurrence of Lewis antigens and the secretor condition. Moreover, histo-blood group antigens (HBGAs) act as attachment factors to the outer viral protein of VP4 for rotavirus. Therefore, in this study, we employed a metabolomic approach to reveal potential signature metabolic molecules and metabolic pathways specific to rotavirus P[8] strain infection (VP4 genotype), which is associated with the expression of HBGA combined secretor and Lewis (Le) phenotypes, specifically secretor/Le(a+b+). Further integration of the achieved metabolomics results with lipidomic and proteomics metadata analyses was performed. Saliva samples were collected from children diagnosed as negative or positive for rotavirus P[8] strain infection (VP4 genotype), which is associated with the HBGA combined secretor/Le(a+b+). A total of 22 signature metabolic molecules that were downregulated include butyrate, putrescine, lactic acid, and 7 analytes. The upregulated metabolic molecule was 2,3-Butanediol. Significant pathway alterations were also specifically observed in various metabolism processes, including galactose and butanoate metabolisms. Butyrate played a significant role in viral infection and was revealed to exhibit different reactions with glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, and fatty acyls. Moreover, butyrate might interact with protein receptors of free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3). The revealed metabolic pathways and molecule might provide fundamental insight into the status of rotavirus P[8] strain infection for monitoring its effects on humans.

Keywords:  butyrate; children; histo-blood group antigens; omics; rotavirus P[8] strain

DOI:  https://doi.org/10.3390/life15050765