bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2025–09–28
nineteen papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology
  1. Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
  2. Pyruvate kinase M2 modulates Japanese encephalitis virus replication in neuronal cells.
  3. The SARS-CoV-2 spike protein interacts with HAX1 to modulate cellular stress responses through activation of the UPR.
  4. Identification of Riboflavin Metabolism Pathway in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3 Protein.
  5. Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
  6. Redox regulation of HIV-1: the thioredoxin pathway, oxidative metabolism, and latency control.
  7. The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.
  8. Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis.
  9. Role of Lipidomics in Respiratory Tract Infections: A Systematic Review of Emerging Evidence.
  10. Autophagy and porcine circovirus infection: a mini review.
  11. Metabolomics and Network Pharmacology Revealed the Mechanism of Feining Mixture Against Respiratory Syncytial Virus Pneumonia.
  12. Hypoxia increases susceptibility of human intestinal epithelial cells to rotavirus infection through repression of interferon induction.
  13. Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.
  14. Hepatitis C virus NS3/4A protease cleaves SPG20, a key regulator of lipid droplet turnover, to promote lipid droplet formation.
  15. ENO2 regulates CD4+ T cell pyroptosis via mitochondrial ROS to drive immunological non-response in HIV infection.
  16. Investigation of Antioxidant Enzymes (GST, GSH, R-GSSG) in Erythrocytes of COVID-19 Patients: A One-Month Observation.
  17. Obesity Risk Factors Promote Metabolic Reprogramming and Viral Infection in Airways with Type 1 High Inflammation.
  18. GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection.
  19. IFN-inducible human phospholipid scramblase 1 (PLSCR1) protein restricts HIV-1 infection by inhibiting membrane fusion.
  1. Nat Microbiol. 2025 Sep 22.
    Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
    Shouheng Jin, Xing He, Zheyu Wang, Tao Zhou, Jun Wang, Guihong Pan, Yin Zhang, Ling Ma, Shuai Yang, Liqiu Wang, Yaoxing Wu, Yilin Zou, Nan Qi, Jun Cui.
      Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.
    DOI:  https://doi.org/10.1038/s41564-025-02107-3
  2. J Gen Virol. 2025 Sep;106(9):
    Pyruvate kinase M2 modulates Japanese encephalitis virus replication in neuronal cells.
    Vijay Singh Bohara, Atharva Deshmukh, Sachin Kumar.
      Japanese encephalitis is a neuroinflammatory condition caused by the Japanese encephalitis virus (JEV). Pyruvate kinase muscle isozyme M2 (PKM2) is a key modulator of glucose metabolism. The role of PKM2 in the autoimmune response and inflammation is now increasingly being acknowledged. However, its role in modulating virus replication has not been explored. In the current study, we have explored the role of PKM2 in JEV replication. Our results show that endogenous PKM2 expression is significantly upregulated in JEV-infected mouse neuroblastoma cells. Moreover, overexpression and knockdown studies substantiate the negative effect of PKM2 on JEV replication. Additionally, JEV infection induced signal transducers and activators of transcription 3 (STAT3) activation in the infected neuronal cells. Overexpression of PKM2 enhanced STAT3 activation, while its downregulation reduced STAT3 activation in the JEV-infected neuronal cells. The results suggested that the overexpression of PKM2 exhibited elevated levels of TNF-α and IL-1β, whereas the downregulation of PKM2 decreased their expression. The in silico studies revealed the potential interaction between PKM2 and non-structural protein 1 (NS1), which was subsequently validated in vitro by co-immunoprecipitation assay. The microscopic studies also unveiled the cellular co-localization of PKM2 and NS1 in the endoplasmic reticulum of infected cells. Altogether, these findings indicate that PKM2 negatively regulates JEV replication by inducing the expression of proinflammatory cytokines such as TNF-α and IL-1β. The study also establishes PKM2 as a binding partner of the NS1 protein. Thus, the study paves the path towards understanding the multifaceted role of PKM2 in JEV pathology.
    Keywords:  Japanese encephalitis virus; non-structural protein; pathogenesis; pyruvate kinase M2; replication
    DOI:  https://doi.org/10.1099/jgv.0.002140
  3. FEBS J. 2025 Sep 21.
    The SARS-CoV-2 spike protein interacts with HAX1 to modulate cellular stress responses through activation of the UPR.
    Tony Avril, Elodie Lafont.
      During cell infection, viruses maintain the lifespan of host cells by preserving key functions of cellular organelles such as the endoplasmic reticulum (ER) and mitochondria to guarantee protein secretion and energy production. The host secretory pathway is rapidly hijacked to produce viral proteins and reconstitute viral particles for further viral dissemination. However, secreted protein synthesis and proper folding are tightly regulated in the host ER to maintain homeostasis, otherwise this organelle is subjected to ER stress that triggers an adaptive response named the unfolded protein response (UPR). The UPR first aims at restoring ER function by producing enzymes to correct or eliminate misfolded proteins. If ER stress remains unresolved, the UPR triggers cell death. In the work published by Zhu et al. in this issue of The FEBS Journal, the authors explore a previously undescribed molecular hijacking function of SARS-CoV-2 to limit host cell death. Indeed, the viral spike protein directly interacts with the host HAX1 molecule to promote UPR activation, limiting the production of deleterious reactive oxygen species and mitochondrial dysfunction to maintain host cell survival.
    Keywords:  ER stress; HAX1; ROS production; SARS‐CoV‐2; cell death; spike
    DOI:  https://doi.org/10.1111/febs.70259
  4. Vet Sci. 2025 Sep 19. pii: 912. [Epub ahead of print]12(9):
    Identification of Riboflavin Metabolism Pathway in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3 Protein.
    Jing Tu, Shengping Wu, Lingjie Wang, Chi Meng, Gengxu Zhou, Jianhua Guo, Jixiang Li, Liting Cao, Zhenhui Song, Hanwei Jiao.
      (1) Background: Hepatitis E (HE) is a novel zoonotic disease caused by hepatitis E virus (HEV). In particular, swine hepatitis E virus (SHEV) genotype IV is one of the main genotypes that infect humans. Open reading frame 3 (ORF3) is an important virulence protein of SHEV, which is involved in virus assembly, release, and regulation of host cell signaling pathways. Circular RNAs (circRNAs), as a type of competitive endogenous RNA (ceRNA), have a closed-loop structure and are special non-coding RNA molecules. They participates in the regulation of multiple biological processes by adsorbing microRNAs (miRNAs). Riboflavin, also known as vitamin B2, is a component of the coenzyme of flavoenzymes in the body. When there is a deficiency of riboflavin, it will affect the biological oxidation process of the host, leading to metabolic disorders. In addition, riboflavin can also affect the synthesis, transportation and decomposition of lipids in the body. It mainly maintains the normal transportation process of fat in the liver. Therefore, the deficiency of riboflavin will lead to the disorder of lipid metabolism in the body. Thus, viral hepatitis is closely related to riboflavin metabolism. However, there are very few reports on SHEV ORF3 affecting the riboflavin metabolism of target cells and thereby influencing viral infection. Therefore, this study investigates this highly significant scientific issue. (2) Methods: In the previous research of our group, adenovirus was used to mediate the overexpression of SHEV ORF3 genotype IV in HepG2 cells. Total RNA was extracted for high-throughput sequencing of circRNAs and transcriptome. KEGG functional enrichment analysis was performed on the data to identify the differentially expressed circRNAs and miRNAs after SHEV infection, and the relevant circRNA-miRNA network in the riboflavin metabolism pathway in HepG2 cells was found. (3) Results: We identified 4 circRNAs in the riboflavin metabolism pathway of HepG2 cells expressing the ORF3 protein of SHEV genotype IV and successfully found 26 relevant circRNA-miRNA networks. (4) Conclusion: We successfully screened and identified circRNAs related to riboflavin metabolism, further identifying the circRNA-miRNA network and its functional targets. For the first time, we investigated the key mechanism by which ORF3 protein influences riboflavin metabolic pathways in target cells through circRNAs, preliminarily revealing that ariboflavinosis can lead to lipid metabolic disorder in the organism. This indicates a close association between viral HE and riboflavin metabolism.
    Keywords:  HepG2 cells; SHEV ORF3; circRNA-miRNA network; riboflavin metabolism pathway; swine hepatitis E virus
    DOI:  https://doi.org/10.3390/vetsci12090912
  5. Annu Rev Virol. 2025 Sep;12(1): 157-178
    Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
    Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian.
      Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.
    Keywords:  antiviral immunity; metabolic pathways; mitochondria; mitochondrial dynamics; oxidative stress; virus
    DOI:  https://doi.org/10.1146/annurev-virology-092623-090901
  6. Front Physiol. 2025 ;16 1651148
    Redox regulation of HIV-1: the thioredoxin pathway, oxidative metabolism, and latency control.
    Jesse F Mangold, Talia H Swartz.
      Redox homeostasis is a critical determinant of HIV-1 pathogenesis, influencing viral entry, transcription, latency, and persistence in distinct cellular reservoirs. The thioredoxin (Trx) system, a central antioxidant pathway, modulates the redox state of transcription factors and viral proteins while buffering oxidative stress. Paradoxically, while oxidative signals can drive HIV-1 gene expression, the virus also co-opts host antioxidant systems, such as thioredoxin (Trx) and glutathione (GSH), to support its replication and survival. In this review, we examine the multifaceted roles of the Trx pathway in HIV-1 infection, highlighting how redox regulation influences transcriptional activation through NF-κB and AP-1, and modulates the function of viral proteins, such as Tat. We further explore how oxidative metabolism intersects with redox balance to influence latency, particularly through cell-type-specific mechanisms in CD4+ T cells and myeloid cells. Emerging insights into thioredoxin-interacting protein (TXNIP) reveal a critical interface between glucose metabolism, ROS signaling, and latency control. Notably, interventions targeting redox homeostasis-whether antioxidant or pro-oxidant-exert divergent effects depending on the cellular reservoir, underscoring the need for tailored therapeutic strategies. By integrating redox biology and immunometabolism, we outline potential avenues to either stabilize latency or induce viral reactivation in pursuit of an HIV-1 cure.
    Keywords:  HIV-1 latency; Tat protein; oxidative metabolism; redox homeostasis; thioredoxin pathway
    DOI:  https://doi.org/10.3389/fphys.2025.1651148
  7. Int J Mol Sci. 2025 Sep 15. pii: 8968. [Epub ahead of print]26(18):
    The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.
    Showkot Ahmed, Réka Dorottya Varga, Jinsung Yang.
      Dengue virus (DENV) is a mosquito-borne flavivirus responsible for a significant global disease burden, especially in tropical and subtropical regions. DENV critically manipulates host cell mitochondria to ensure its replication and survival. The clinical manifestations are well-studied and how dengue infection significantly alters the mitochondrial dynamics, and the subsequent functional cellular homeostasis has been unveiled. This review discusses the strategies by which DENV alters mitochondrial functions and dynamics. It particularly focuses on the virus-induced suppression of mitochondrial quality control mechanisms like mitophagy. Moreover, the dichotomous role of mitophagy in supporting DENV replication is highlighted. By incorporating recent studies about DENV-host interactions at the mitochondrial interface, mitochondria, as regulators and targets in dengue pathogenesis, are suggested as possible molecular targets for therapeutic intervention.
    Keywords:  biogenesis; cellular homeostasis; dengue virus; mitochondria; mitochondrial bioenergetics; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/ijms26188968
  8. Metabolites. 2025 Sep 11. pii: 608. [Epub ahead of print]15(9):
    Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis.
    Mohammad Mehdi Banoei, Abdulrazagh Hashemi Shahraki, Kayo Santos, Gregory Holt, Mehdi Mirsaeidi.
       BACKGROUND: This study aimed to analyze metabolic changes in blood samples from patients with confirmed COVID-19 to explore the correlation between metabolomics and cytokines in survivors and non-survivors of SARS-CoV-2 infection. Understanding the complex biochemical and immunometabolic mechanisms underlying SARS-CoV-2 infection is essential for elucidating the pathophysiology and virulence of COVID-19.
    METHODS: This study included 40 hospitalized COVID-19 patients and 40 healthy controls. Serum metabolic profiles were analyzed using ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS), and cytokine levels were measured using ELISA.
    RESULTS: Our study defined three clear metabolic phenotypes among survivors and non-survivors of COVID-19 compared with healthy controls, which might be related to mortality, severity, and disease burden. A strong relationship was observed between certain inflammatory markers, including IL-1β, IL-2, IFN-β, IFN-γ, IL-17, and GM-CSF, as well as several metabolites, particularly in COVID-19 non-survivors, such as LysoPCs, 3-hydroxykynurenine, and serotonin. Different metabolite-cytokine correlation patterns were observed according to patient outcomes, indicating unique correlations between metabolic and immune responses in survivors and non-survivors. Metabolic phenotypes were associated with clinical outcomes, comorbidities, and sex-related differences. Kynurenine and related metabolites of tryptophan metabolism were closely correlated with COVID-19 severity, age, and mortality. Compared with survivors and healthy controls, non-survivors displayed higher IL-6, together with distinct metabolic changes. These included increased kynurenine through the IDO1 pathway, elevated glucose and lactate reflecting hyperglycolysis and energy stress, and higher xanthosine from purine turnover. Stronger cytokine-metabolite correlations in this group point to tightly linked immunometabolic activation.
    CONCLUSIONS: Metabolomic profiling revealed distinct metabolic phenotypes that could be associated with the severity and inflammation levels of COVID-19. Correlation analysis between metabolites and cytokines demonstrated strong intercorrelations between specific metabolites and cytokines, indicating a strong interrelationship between inflammatory markers and metabolic alterations. Specific metabolic pathways associated with cytokines and their clinical relevance may serve as potential therapeutic targets.
    Keywords:  COVID-19; cytokines biosignatures; immunometabolism; metabolic biosignatures; metabolites-cytokine correlation
    DOI:  https://doi.org/10.3390/metabo15090608
  9. Microorganisms. 2025 Sep 19. pii: 2190. [Epub ahead of print]13(9):
    Role of Lipidomics in Respiratory Tract Infections: A Systematic Review of Emerging Evidence.
    Vasiliki E Georgakopoulou, Konstantinos Dodos, Vassiliki C Pitiriga.
      Lower respiratory tract infections (LRTIs) remain a major cause of global morbidity and mortality, yet accurate pathogen identification and risk stratification continue to pose clinical challenges. Lipidomics-the comprehensive analysis of lipid species within biological systems-has emerged as a promising tool to unravel host-pathogen interactions and reveal novel diagnostic and prognostic biomarkers. This systematic review synthesizes evidence from nine original studies applying mass spectrometry-based lipidomic profiling in human LRTIs, including community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), and coronavirus disease 2019 (COVID-19). Across diverse study designs, sample types, and analytical platforms, consistent alterations in lipid metabolism were observed. Perturbations in phospholipid classes, particularly phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs), were frequently associated with disease severity and immune activation. The ratios of PC to LPC and phosphatidylethanolamine (PE) to lysophosphatidylethanolamine (LPE) emerged as markers of inflammatory remodeling. Sphingolipids-including sphingomyelins (SMs) and sphingosine-1-phosphate (S1P)-were identified as key modulators of monocyte and neutrophil activation. Fatty acid-derived lipid mediators such as oxylipins (e.g., 12,13-epoxyoctadecenoic acid and 15-hydroxyeicosatetraenoic acid) and acylcarnitines reflected pathogen-specific immune responses and mitochondrial dysfunction. Several lipid-based classifiers demonstrated superior diagnostic and prognostic performance compared to conventional clinical scores, including the CURB-65 and pneumonia severity index. However, significant heterogeneity in experimental design, lipid identification workflows, and reporting standards limits inter-study comparability. While preliminary findings support the integration of lipidomics into infectious disease research, larger multi-omic and longitudinal studies are required. This review provides the first comprehensive synthesis of lipidomic alterations in human LRTIs and highlights their emerging translational relevance.
    Keywords:  biomarkers; lipidomics; phosphatidylcholines; pneumonia; respiratory tract infections; sphingolipids
    DOI:  https://doi.org/10.3390/microorganisms13092190
  10. Front Cell Infect Microbiol. 2025 ;15 1667956
    Autophagy and porcine circovirus infection: a mini review.
    Xiaoyong Chen, Xi Chen, Ziding Yu.
      Porcine circovirus (PCV), particularly PCV type 2 (PCV2), is a major pathogen driving porcine circovirus-associated diseases (PCVAD), causing significant economic losses in the swine industry. Accumulating evidence highlights autophagy as a critical host-pathogen interface during PCV infection. PCV2 activates autophagy through reactive oxygen species (ROS)-mediated signaling and metabolic regulators like the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) axis, creating a conducive environment for viral persistence. Concurrently, this virus exploits ubiquitin ligases to induce ubiquitination of cellular immune factors, promoting selective autophagy for immune evasion. Host factors, such as retinol-binding protein 4 (RBP4), act as restriction factors by counteracting viral strategies through autophagy modulation. Environmental stressors could exacerbate PCV2 pathogenesis by amplifying ROS-dependent autophagy, while interventions like taurine mitigate viral replication via ROS/AMPK/mTOR pathway inhibition. This mini-review synthesizes current understandings of PCV-autophagy crosstalk, emphasizing its critical role as a host vulnerability and therapeutic target. Understanding the intricate interplay between autophagy and PCV infection may unveil novel therapeutic targets, such as autophagy modulators, to mitigate viral replication and immune pathology.
    Keywords:  autophagy; porcine circovirus; viral pathogenesis; viral replication; virus-host interaction
    DOI:  https://doi.org/10.3389/fcimb.2025.1667956
  11. Basic Clin Pharmacol Toxicol. 2025 Oct;137(4): e70114
    Metabolomics and Network Pharmacology Revealed the Mechanism of Feining Mixture Against Respiratory Syncytial Virus Pneumonia.
    Chengdou Xie, Qianyu Liu, Ping Lan, Linxiu Peng, Siqing Chen.
      Respiratory syncytial virus (RSV) is a leading etiological agent of pneumonia, particularly affecting infants under 2 years and elderly populations, with characteristic clinical manifestations including fever, cough and wheezing. Although Feining mixture-a traditional Chinese medicine formulation based on the classical Maxing Shigan Decoction from the 'Treatise on Febrile Diseases'-has shown clinical efficacy in ameliorating symptoms of viral pneumonias including RSV infection, its precise pharmacological mechanisms remain undefined. Through serum metabolomics and network pharmacology approaches, we systematically identified RSV-associated metabolic disturbances and characterised Feining mixture's regulatory effects on these pathological alterations. Our investigations revealed that Feining mixture significantly attenuated pulmonary inflammation, as evidenced by reduced pro-inflammatory cytokine levels in bronchoalveolar lavage fluid and improved histopathological features in RSV-infected mice. Metabolomic profiling identified 49 differentially expressed metabolites and 14 perturbed metabolic pathways. Network pharmacology and molecular docking analyses predicted the involvement of TP53, AKT1 and STAT3 as core targets, suggesting modulation of PI3K/AKT and TNF signalling pathways. These predictions were experimentally validated through qPCR and Wb analyses, which confirmed that Feining mixture's therapeutic effects are mediated through selective inhibition of the PI3K/AKT1 signalling cascade. These findings provide novel mechanistic insights into Feining mixture's anti-RSV activity, establishing its therapeutic potential through multi-target modulation of critical inflammatory and metabolic pathways.
    Keywords:  Feining mixture; metabolomics; molecular docking; network pharmacology; respiratory syncytial virus
    DOI:  https://doi.org/10.1111/bcpt.70114
  12. Gut Microbes. 2025 Dec;17(1): 2560593
    Hypoxia increases susceptibility of human intestinal epithelial cells to rotavirus infection through repression of interferon induction.
    Sorin O Jacobs, Stephanie Muenchau, Zina M Uckeley, Gianna V Passarelli, Asher David, Skyler Briggs, James M Burke, Megan L Stanifer, Steeve Boulant.
      Intestinal epithelial cells (IECs) serve as both a physical barrier and a source of robust antiviral interferon (IFN) response. As such, they constitute the primary barrier that enteric viruses, such as rotavirus, need to overcome to initiate infection. The gut is characterized by very low oxygen levels (hypoxia) within the lumen, resulting in a unique hypoxic physiological environment in which rotavirus infection occurs. Depending on the tissues or viruses, conflicting results have been described for the role of hypoxia in regulating viral infections, where hypoxia could have either a proviral or antiviral function. Since intestinal epithelial cells naturally exist in a hypoxic environment, it is essential to investigate how these conditions affect rotavirus infection. We found that hypoxia promotes rotavirus infection, resulting in increased virus replication and production of infectious virus particles. We showed that this increased production of rotavirus particles under hypoxia is due to a decreased induction of IFNs, leading to a decreased expression of IFN stimulated genes and antiviral protection. RNA sequencing showed a robust decrease in ISG production in hypoxia for both rotavirus infection and poly I:C transfection, suggesting a conserved inhibition of IECs' IFN response to viral pathogen challenges under hypoxic conditions. Functional analyses revealed that hypoxia impairs signal transduction leading to IFN expression by negatively regulating the activation of the master signaling molecule TBK1. Mechanistically, we determined that hypoxia induces the expression of the protein phosphatase PP2A which is responsible for the hypoxia-induced impairment of TBK1 activation. Importantly, we confirmed that this hypoxia-mediated dampening of immune response was not restricted to rotavirus infection but dampened the IFN induction of a broad range of viruses and immune stimuli. Together, we propose that hypoxia creates an immune-suppressive environment through downregulation of IFN, representing a novel proviral mechanism for hypoxia in the human gastro-intestinal tract.
    Keywords:  Intestinal epithelial cells; antiviral response; hypoxia; intestinal organoids; rotavirus; type III interferon
    DOI:  https://doi.org/10.1080/19490976.2025.2560593
  13. Biomolecules. 2025 Sep 18. pii: 1339. [Epub ahead of print]15(9):
    Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.
    Eunseuk Lee, Adaobi Amelia Ozigbo, Joseph Varon, Mathew Halma, Madison Laezzo, Song Peng Ang, Jose Iglesias.
      Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes.
    Keywords:  SARS-CoV-2; autophagy; biomarkers; long COVID; mitochondrial dysfunction; mitochondrial reactive oxygen species; mitophagy
    DOI:  https://doi.org/10.3390/biom15091339
  14. J Virol. 2025 Sep 23. e0089025
    Hepatitis C virus NS3/4A protease cleaves SPG20, a key regulator of lipid droplet turnover, to promote lipid droplet formation.
    Chieko Matsui, Putu Yuliandari, Lin Deng, Takayuki Abe, Ikuo Shoji.
      Hepatitis C virus (HCV) assembles in close proximity to lipid droplets (LDs), which play important roles in HCV RNA replication. HCV infection often causes the accumulation of large LDs in hepatocytes. However, the molecular mechanism underlying HCV-induced large LD formation is poorly understood. It has been reported that the SPG20/Spartin protein associates with the LD surface and plays a crucial role in LD turnover by recruiting the ubiquitin ligase Itch to promote the ubiquitin-dependent degradation of adipophilin (ADRP), which protects LDs from lipase-mediated degradation. To elucidate the mechanism underlying HCV-induced large LD formation, we investigated the SPG20 protein's role in LD formation in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV infection promoted SPG20 protein cleavage. Transfection of increasing amounts of NS3/4A, but not the inactive NS3/4A mutant, resulted in SPG20 cleavage, implicating the NS3/4A protease in this cleavage. Site-directed mutagenesis suggested that the NS3/4A protease cleaves SPG20 at Cys504 and Cys562. The SPG20 protein was co-immunoprecipitated with the LD-attached protein TIP47. Increasing amounts of NS3/4A protease, but not inactive NS3/4A, decreased the co-precipitation of SPG20 with TIP47. The siRNA-mediated knockdown of Itch in Huh-7.5 cells restored ADRP levels, suggesting that Itch mediates ubiquitylation-dependent ADRP degradation. Immunofluorescence staining of HCV-infected cells revealed that ADRP was localized mainly around LDs in HCV-infected cells, whereas cytosolic ADRP was decreased. We propose that the HCV NS3/4A protease specifically cleaves SPG20 and inhibits Itch-mediated ubiquitin-dependent degradation of LD-associated ADRP, thereby promoting the formation of large LDs.IMPORTANCEHCV infection often promotes the formation of large LDs in HCV-infected cells. However, the molecular mechanism underlying large LD formation is poorly understood. LD turnover is regulated by SPG20, Itch E3 ligase, and ADRP. To elucidate the mechanism underlying the formation of large LDs induced by HCV infection, we investigated the roles of SPG20, Itch, and ADRP in large LD formation. The HCV NS3/4A protease specifically cleaves SPG20 and disrupts Itch recruitment to LD-associated ADRP. Therefore, LD-associated ADRP can escape and protects LDs from lipase-mediated degradation, thereby promoting LD growth. We propose that HCV NS3/4A protease-mediated cleavage of SPG20 contributes to a previously uncharacterized mechanism underlying the formation of large LDs in HCV-infected cells. These findings may lead to a better understanding of how the virus forms large LDs in infected cells.
    Keywords:  Itch; NS3/4A protease; SPG20; adipophilin; hepatitis C virus; lipid droplet
    DOI:  https://doi.org/10.1128/jvi.00890-25
  15. mBio. 2025 Sep 25. e0170225
    ENO2 regulates CD4+ T cell pyroptosis via mitochondrial ROS to drive immunological non-response in HIV infection.
    Siyao Li, Heqiao Wang, Pan Wang, Tianling Yang, Jiaqi Li, Mei Liu, Yajing Fu, Yongjun Jiang, Zining Zhang, Hong Shang.
      Approximately 10-40% of patients with acquired immune deficiency syndrome (AIDS) fail to restore the number of CD4+ T cells after antiretroviral therapy (ART). They are referred to as immunological non-responders (INRs) and have increased morbidity and mortality of AIDS and non-AIDS events. Pyroptosis is one of the key factors driving CD4+ T cell death in human immunodeficiency virus (HIV) infection, but its relationship with immune reconstitution and the underlying mechanisms is poorly understood. Through our in vitro experiments, we showed that the expression of enolase 2 (ENO2) decreased in INRs and inhibited ENO2-enhanced CD4+ T cell pyroptosis through the regulation of reactive oxygen species (ROS). Furthermore, we discovered that supplementation with phosphoenolpyruvate (PEP), the catalytic product of ENO2, could restore mitochondrial function and reduce the pyroptosis of CD4+ T cells. Our study clarified the ENO2-PEP-ROS-pyroptosis axis of CD4+ T cells in INRs and provided a novel therapeutic target for enhancing immune reconstitution in HIV infection.IMPORTANCEThe decrease in CD4+ T cell count is an important cause of poor immune reconstitution in HIV-infected patients. In this study, we analyzed the pyroptosis of T cells in HIV-infected patients with poor immune reestablishment and demonstrated how ENO2, a key enzyme in the glycolytic pathway, affects pyroptosis through mitochondrial ROS. Our results clarified the role of ENO2 in regulating CD4+ T cell pyroptosis in INRs and discussed its possible mechanism. This provides a new target for improving immune reconstitution and intervention in HIV infection.
    Keywords:  ENO2; HIV; immune response; mitochondrial ROS; pyroptosis
    DOI:  https://doi.org/10.1128/mbio.01702-25
  16. J Inflamm Res. 2025 ;18 12783-12800
    Investigation of Antioxidant Enzymes (GST, GSH, R-GSSG) in Erythrocytes of COVID-19 Patients: A One-Month Observation.
    Elżbieta Cecerska-Heryć, Natalia Serwin, Ewa Pius-Sadowska, Klaudia Głowacka, Aleksandra Polikowska, Małgorzata Goszka, Radosław Birger, Marta Budkowska, Bogusław Machaliński, Barbara Dołęgowska.
       Introduction: Oxidative stress (OS) occurs when there is an imbalance between reactive oxygen species (ROS) production and the body's ability to neutralize them. This can lead to cellular damage and is associated with aging and various diseases. Glutathione (GSH) acts as a vital non-enzymatic antioxidant, while enzymes such as glutathione S-transferase (GST) and glutathione reductase (GR) help maintain the body's redox balance. OS from viruses, including coronavirus, can disrupt inflammation regulation and cause prolonged tissue damage.
    Aim: This study examines GSH levels and the activities of GST and R-GSSG in the erythrocytes of COVID-19 patients compared to those of healthy controls.
    Materials and Methods: The study involved 85 COVID-19 patients (42 females and 43 males), with blood samples collected at the time of disease detection and at 7, 14, and 28 days later. The control group included 85 healthy individuals. Antioxidant levels (GSH, GST, R-GSSG) were measured using spectrophotometric methods.
    Results: COVID-19 patients exhibited a significant decrease in GSH concentration (p < 0.001) and an increase in R-GSSG (p < 0.001) and GST (p = 0.046) activity. Lower GSH levels correlated with a higher risk of death (p = 0.008). Multivariate analysis revealed relationships between GSH and factors such as time since detection, survival rate, hospital stay, and disease severity.
    Conclusion: COVID-19 disrupts antioxidant enzyme balance, potentially worsening disease severity and increasing mortality risk, especially in older patients.
    Keywords:  COVID-19; GSH; GST; R-GSSG oxidative stress; antioxidant enzymes
    DOI:  https://doi.org/10.2147/JIR.S523607
  17. Biomolecules. 2025 Aug 26. pii: 1229. [Epub ahead of print]15(9):
    Obesity Risk Factors Promote Metabolic Reprogramming and Viral Infection in Airways with Type 1 High Inflammation.
    Paige Hartsoe, Niccolette Schaunaman, Taylor Nichols, Diana Cervantes, Stephanie Dawrs, Fernando Holguin, Hong Wei Chu.
      Obesity is a significant health issue, as it is related to human diseases such as asthma and respiratory viral infections. Asthma patients with obesity have more severe diseases, which can be presented with type 1 (e.g., IFN-γ) high inflammation. The interactions of obesity or saturated fatty acids (e.g., palmitic acid, PA) with IFN-γ in airway viral infections have not been clear. In this study, we determined the role of obesity risk factors high-fat diet (HFD) and PA in rhinovirus infection in the context of IFN-γ stimulation in mice and cultured human tracheobronchial epithelial cells. We further examined the therapeutic effect of a glycolytic inhibitor on metabolic reprogramming and viral infection in our experimental models. In mice, HFD in combination with IFN-γ significantly increased lung rhinovirus levels as well as neutrophilic inflammation. Similarly, PA and IFN-γ combination increased viral infection in mice, but HFD or PA alone had a minimal effect on viral infection. Mouse model data were confirmed in cultured primary healthy human airway epithelial cells where PA and IFN-γ together increased viral load. Mechanistically, HFD or PA in combination with IFN-γ up-regulated the glycolytic pathway and generated metabolites favoring viral replication. Inhibition of glycolysis by 2-DG effectively reduced viral infection in human airway epithelial cells. Our data suggest that hosts with obesity along with type 1 high inflammation may be at an increased risk of respiratory viral infections. Intervention of the glycolytic pathway or its metabolites may reduce the severity of viral infection.
    Keywords:  asthma; high-fat diet; interferon-gamma; metabolic reprogramming; obesity; palmitic acid; rhinovirus
    DOI:  https://doi.org/10.3390/biom15091229
  18. J Virol. 2025 Sep 24. e0128825
    GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection.
    Luiza A Castro Jorge, Daniel F Edwards, Rosario Labastida, Danielle E Goodman, Estela A Pereira, Oded Foreman, Katherine R Spindler.
      The integrated stress response (ISR) is a cellular signaling pathway that reduces protein synthesis in the face of cellular stress, including viral infection. Two eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and general control nonderepressible 2 (GCN2), are commonly activated during viral infections. Mouse adenovirus type 1 (MAV-1) infection leads to a steep reduction of PKR levels by proteasomal degradation. We assayed whether GCN2, a sensor of amino acid starvation and UV damage, plays a role in the ISR to MAV-1 infection. There was more phosphorylated GCN2 in MAV-1-infected cells, and its activation was dependent on virus replication since UV-inactivated virus was not able to increase the phosphorylation of GCN2. Infected Eif2ak4tm1.2Dron mice (designated here Gcn2-/- mice) had lower survival than wild-type (WT) mice, but results indicated that this was not due to increased viral replication. Both Gcn2-/- and WT mice developed multifocal brain parenchymal microhemorrhages during infection. While Gcn2-/- animals had more lesions, their higher mortality is likely not due to the microhemorrhages alone. Cytokine RNA and protein assays of WT and Gcn2-/- mice only showed a difference for IL- β levels, which were higher in Gcn2-/- mice. Our results also indicate that of the two eIF2α kinases, PKR and GCN2, GCN2 is the primary inducer of phosphorylated-eIF2α during MAV-1 infection. GCN2 is thus antiviral and contributes to the host response to MAV-1 infection.IMPORTANCECells often respond to viral infection by activation of the host protein kinase R (PKR), part of the integrated stress response (ISR). We show that a second host protein kinase, general control nonderepressible 2 (GCN2), is activated by phosphorylation in response to mouse adenovirus type 1 (MAV-1) infection. Our results indicate GCN2 is antiviral: without it, the mortality in MAV-1-infected mouse is higher. Furthermore, the data show that GCN2, rather than PKR, is the main inducer of eIf2α phosphorylation (and thus the ISR) upon MAV-1 infection. This is consistent with PKR exerting antiviral effects in MAV-1 infections through a pathway independent of eIf2α phosphorylation.
    Keywords:  PKR; general control nonderepressible 2; integrated stress response; protein kinase R
    DOI:  https://doi.org/10.1128/jvi.01288-25
  19. Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2516527122
    IFN-inducible human phospholipid scramblase 1 (PLSCR1) protein restricts HIV-1 infection by inhibiting membrane fusion.
    Yajie Liu, Pei Li, Yi-Min Zheng, Yuta Hikichi, Sherimay D Ablan, Eric O Freed, Shan-Lu Liu.
      Human phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that inhibits viral infections through various mechanisms. Here, we identify PLSCR1 as a host restriction factor that inhibits HIV-1 entry by impairing membrane fusion mediated by the envelope glycoprotein (Env). Using multiple cell types including the human SupT1 T cell line and purified CD4+ T cells, we demonstrate that PLSCR1 inhibits the replication of HIV-1 with diverse tropisms and subtypes, as well as HIV-2 and SIV. Mechanistically, we find that PLSCR1 blocks viral entry and cell-to-cell transmission, in part by restricting HIV-1 virion-cell and cell-cell fusion without affecting CD4 or CXCR4 expression or virus binding to the cell surface. Collectively, these findings establish PLSCR1 as a broad-spectrum lentiviral restriction factor that acts at the membrane fusion stage, thereby expanding our understanding of ISG-mediated antiviral defense.
    Keywords:  HIV; PLSCR1; entry; membrane fusion; restriction factor
    DOI:  https://doi.org/10.1073/pnas.2516527122
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