bims-mevinf 2026-01-11 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2026–01–11
fifteen papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

Metabolic hijackers: how viral proteins redefine host cell landscapes.
Mitochondrial and lipid metabolism rewiring during HEV infection.
Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis.
Seneca Valley virus 3C protease targets the Nrf2/HO-1 pathway to antagonize its antiviral activity.
Viral reprogramming of glial metabolism as a driver of neuroinflammation.
Metabolomics in influenza viral infection: insights into host-virus interactions and potential biomarkers of severe outcomes.
Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication.
Zika Virus Reprograms Microglial Mitochondrial Metabolism to Support Immune Activation and Viral Replication: Omega-3 DHA Counteracts Neuroinflammation and Viral Persistence.
Grass carp retinoid-related orphan receptor α (gcRORαa) promotes GCRV replication via LDLR-mediated lipid accumulation.
Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.
Glucose Metabolism and Innate Immune Responses in Influenza Virus Infection: Mechanistic Insights and Clinical Perspectives.
Lipidomic profiling of influenza A virus production in MDCK cells towards targeted clone selection.
Analysis of the impact of SARS-CoV-2 infection on immune function and metabolic changes in college students.
Tetrandrine-driven autophagy suppresses SARS-CoV-2 replication by modulating cholesterol and IGF signaling pathways.
Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity.

J Virol. 2026 Jan 09. e0055625

Metabolic hijackers: how viral proteins redefine host cell landscapes.

Adam Hafner, Rebekah L Mokry, John G Purdy, Christiane E Wobus.

  Viruses are metabolic engineers of host cells. As obligate intracellular pathogens, they rely on host cell metabolism for efficient viral replication. The manipulation of host metabolic processes is a strategy shared among diverse virus families to secure the necessary resources for replicating new genomes, building more virus particles, and supporting cell growth and proliferation. Key metabolic pathways targeted by viruses for disruption and manipulation are glycolysis, glutaminolysis, and lipid metabolism. However, the mechanisms behind virus-induced metabolic reprogramming and the viral proteins mediating it remain poorly understood. This review explores how specific viral proteins reshape the metabolic milieu of host cells during viral infections. We also highlight common themes and outline gaps in knowledge to stimulate further investigations into how viral proteins manipulate host metabolism. Such mechanistic insights will deepen our understanding of virus-host interactions and may reveal novel therapeutic targets.

Keywords:  RNA and DNA virus proteins; cellular metabolism; glutaminolysis; glycolysis; lipid metabolism

DOI:  https://doi.org/10.1128/jvi.00556-25
Cell Mol Life Sci. 2026 Jan 08.

Mitochondrial and lipid metabolism rewiring during HEV infection.

Quentin Glaziou, Qian Chen, Jordi Gouilly, Ming Wu, Marie Duhamel, Michel Salzet, Jacques Izopet, Reem Al Daccak, Hicham El Costa, Nabila Jabrane-Ferrat.

  Hepatitis E virus (HEV), a leading cause of acute and chronic viral hepatitis, poses a persistent global health challenge. A deeper mechanistic understanding of virus-host interactions is critical for identifying therapeutic targets to mitigate HEV-associated disease. In this study, we employ a systems biology framework to comprehensively map metabolic and bioenergetic alterations induced by HEV genotypes 1 and 3 in HepG2/C3a-MAVS-KD cells, a robust model of HEV infection, enabling reliable assessment of virus- and host-driven cellular changes. Our analyses reveal extensive remodelling of host metabolism, including reprogramming of the tricarboxylic acid (TCA) cycle, mitochondrial oxidative phosphorylation (OXPHOS), fatty acid metabolism, and β-oxidation-pathways that collectively sustain the energetic and biosynthetic demands of viral infection. HEV infection also reshapes the cellular lipidome, increasing levels of long-chain neutral lipids and lipid droplet abundance, alongside elevated levels of pro-inflammatory oxylipins. Functional metabolic assays demonstrate a reliance on lipid-fuelled OXPHOS rather than glycolysis for efficient HEV infection. These findings uncover critical host metabolic dependencies exploited by HEV and offer a conceptual framework for targeting metabolic hubs as a therapeutic strategy against HEV infection. Author Summary: Viruses are obligate intracellular pathogens that reprogramme host cellular machinery to their advantage. Yet, the extent to which Hepatitis E virus (HEV) infection orchestrates metabolic reprogramming, and the implications of these changes for viral fitness, remain poorly defined. By integrating large-scale proteomics with lipid metabolic profiling, we delineate molecular strategies through which HEV subverts host lipid metabolism and mitochondrial function. Our findings provide mechanistic insight into how HEV infection modulates host metabolic pathways to its advantage, highlighting potential targets for therapeutic intervention.

Keywords:  Hepatitis e virus infection; Host cell metabolism; Lipids; Mitochondria

DOI:  https://doi.org/10.1007/s00018-025-05994-1
Redox Biol. 2026 Jan 05. pii: S2213-2317(26)00006-6. [Epub ahead of print]89 104008

Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis.

Yafang Xu, Jinqiu Zhang, Chengwei Yin, Laizhen Liu, Zhenglei Wang, Shaodong Fu, Rong Fan, Yanyan Zhao, Jinfeng Miao.

  Porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, causes recurrent outbreaks of severe enteric disease, posing a significant threat to the global swine industry. The persistent challenge highlights the urgent need for a deeper understanding of host-virus interactions to improve prevention and control strategies. Here, we demonstrated that PEDV infection reprogrammed host metabolism toward aerobic glycolysis, a metabolic shift that not only facilitated viral replication but also established an immunosuppressive microenvironment. PEDV infection activated the hypoxia-inducible factor-1α (HIF-1α) pathway and induced mitochondrial dysfunction, leading to the accumulation of mitochondrial reactive oxygen species (mROS), which in turn stabilized HIF-1α, creating a positive feedback loop that amplified glycolytic gene expression and lactate production. We confirmed that glycolysis was essential for PEDV replication, and that elevated glucose levels enhanced replication efficiency. Furthermore, PEDV-induced glycolysis and lactate accumulation inhibited the generation of interferons (IFNs), thereby facilitating immune evasion. Collectively, our findings revealed a metabolic-immune axis exploited by PEDV to optimize viral replication and subvert host defenses. This study not only provides novel insights into the metabolic adaptations underlying PEDV pathogenesis but also highlights host metabolic pathways as potential therapeutic targets to combat PEDV and other related coronaviruses.

Keywords:  Glycolysis; HIF-1α; Metabolism; Mitochondria; Porcine epidemic diarrhea virus; ROS

DOI:  https://doi.org/10.1016/j.redox.2026.104008
J Virol. 2026 Jan 05. e0165625

Seneca Valley virus 3C protease targets the Nrf2/HO-1 pathway to antagonize its antiviral activity.

Jiangwei Song, Teng Liu, Jingjing Yang, Liwei Zhao, Jiayao Su, Zijian Li, Ruiyi Ma, Xuexia Wen, Peipei Cheng.

  Seneca Valley virus (SVV) infection gives rise to severe vesicular diseases in pigs, presenting a substantial threat to the global swine industry. The redox imbalance resulting from oxidative stress is an essential pathogenic mechanism during viral infections. Nevertheless, the regulatory mechanisms of oxidative stress by viral and host factors during SVV infection remain elusive. In this study, we discovered that SVV elicited cellular oxidative stress through the induction of reactive oxygen species production and the suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Our findings indicated that the overexpression of Nrf2/HO-1 exerted a remarkable anti-SVV effect. Conversely, the inhibition of Nrf2/HO-1 expression facilitated the proliferation of SVV. HO-1 metabolic products carbon monoxide and biliverdin inhibit SVV replication. HO-1 promotes type I interferon response and interferon-stimulated gene expressions, which contribute to its antiviral mechanism. Furthermore, our findings reveal that the SVV 3C proteinase targets the Nrf2/HO-1 axis for degradation via caspase pathway, thereby promoting viral replication. Collectively, these results clarify the convoluted molecular mechanisms by which SVV weakens the host's antioxidant defense system and suggest potential targets for therapeutic interventions regarding SVV infections.
IMPORTANCE: Nrf2 is a crucial redox regulator responsible for initiating the expression of downstream antioxidant genes, including HO-1 and superoxide dismutase. HO-1, an enzyme induced by stress, performs protective roles through the conversion of heme into carbon monoxide, biliverdin, and iron. Nevertheless, the function of Nrf2/HO-1 during Seneca Valley virus (SVV) infection is yet to be clearly defined. In this study, we showed that SVV infection led to a reduction in the expression of Nrf2/HO-1, and the overexpression of Nrf2/HO-1 induced a potent anti-SVV effect. SVV 3C proteinase promoted the caspase-dependent degradation of Nrf2/HO-1. As a result, it attenuated the cell's ability to resist oxidative stress and counteracted the antiviral function of Nrf2/HO-1. Our research further uncovered a novel mechanism through which SVV eludes the host's antiviral effects by disrupting cellular redox balance, offering important targets for preventing and controlling SVV infection.

Keywords:  3C protease; Seneca Valley virus (SVV); heme oxygenase-1 (HO-1); nuclear factor erythroid 2-related factor 2 (Nrf2)

DOI:  https://doi.org/10.1128/jvi.01656-25
Front Immunol. 2025 ;16 1686774

Viral reprogramming of glial metabolism as a driver of neuroinflammation.

Tamara Rodrigues, Gabriel Salles Beltrão, Heloísa Girardi, Aguinaldo R Pinto.

  Considerable attention has been recently devoted to the involvement of immune cells in the central nervous system (CNS) during infections with neurotropic viruses, such as SARS-CoV-2, HIV-1, and ZIKV. These viruses are capable of infecting astrocytes and microglia, the main glial cells in the CNS, responsible for regulating neuronal activity. Here, we discuss how viral infections lead to metabolic reprogramming toward aerobic glycolysis in these cells, enhancing pro-inflammatory pathways, such as inflammasome activation, resulting in the secretion of inflammatory cytokines that favor the development of neuroinflammation. In this mini review, we discuss the pivotal interplay between metabolism and immunity towards viral pathogenesis in the CNS, pointing out the relevance of therapeutic strategies targeting both metabolic and immunological pathways to enhance antiviral and neuroprotective responses.

Keywords:  CNS; glial cells; inflammasome; metabolic reprogramming; neuroinflammation; neurotropic viruses

DOI:  https://doi.org/10.3389/fimmu.2025.1686774
Crit Rev Microbiol. 2026 Jan 04. 1-22

Metabolomics in influenza viral infection: insights into host-virus interactions and potential biomarkers of severe outcomes.

Chen Liu, Qingyun Ma, Yong Yang, Rong Rong.

  Influenza viruses are highly contagious respiratory pathogens that cause seasonal outbreaks, leading to millions of infections and a significant number of deaths worldwide. To support rapid replication and transmission, influenza viruses hijack the host's metabolic pathways, including those involved in carbohydrate, amino acid, and lipid metabolism. Through this metabolic reprogramming, the virus leverages the host's metabolic resources to produce viral components and create specialized compartments necessary for replication and dissemination. In response, host cells activate a range of metabolic defense mechanisms to detect and counteract the virus-induced metabolic changes, resulting in a dynamic interplay that profoundly impacts the outcome of the infection. Advances in metabolomics have provided valuable insights into these complex host-virus interactions, identifying key metabolic biomarkers with potential for early diagnosis, real-time disease monitoring, and therapeutic response evaluation, especially in the early detection and management of severe influenza infections. In the future, these metabolic biomarkers could drive the development of new strategies for influenza prevention and treatment, providing a scientific foundation for precision medicine.

Keywords:  Influenza virus; host–virus interactions; metabolic reprogramming; metabolomic biomarkers; severe influenza outcomes

DOI:  https://doi.org/10.1080/1040841X.2025.2601028
J Virol. 2026 Jan 09. e0173625

Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication.

Shuting Zhou, Houde Zhao, Junrui Zhu, Yanjun Zhou, Zhibiao Yang, Zhe Wang.

  Porcine epidemic diarrhea virus (PEDV) causes acute intestinal disease in pigs and remains a major threat to the global swine industry due to its high morbidity and mortality in neonatal piglets. To investigate host metabolic alterations upon PEDV infection, we performed untargeted metabolomic profiling in LLC-PK1 and Vero E6 cells. Pathway enrichment analysis revealed significant changes in nucleotide metabolism, cofactor biosynthesis, amino acid biosynthesis, and purine metabolism. Notably, PEDV infection led to divergent regulation of purine metabolism in the two cell types-upregulation in Vero E6 cells and downregulation in LLC-PK1 cells at 18 h post-infection. We further identified inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, as a critical host factor for PEDV replication. Both genetic knockdown of IMPDH2 and pharmacological inhibition using merimepodib (VX-497, MMPD) significantly reduced viral RNA levels and impaired replication. These treatments also suppressed host nucleotide biosynthetic activity. Together, our findings demonstrate that PEDV hijacks the IMPDH-dependent guanosine biosynthesis pathway to support its replication and identify IMPDH as a promising host-directed antiviral target against PEDV.
IMPORTANCE: PEDV poses a major global threat to swine health. This study uncovers a key mechanism of pathogenesis: PEDV exploits host nucleotide metabolism, inducing significant reprogramming with emphasis on purine biosynthesis. Comparative infection of porcine (LLC-PK1) and primate (Vero E6) cells revealed cell-specific metabolic adaptations. Crucially, we identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for guanosine biosynthesis, as an essential host dependency factor for PEDV replication. Inhibiting IMPDH genetically or pharmacologically significantly reduced viral titers, validating it as a critical vulnerability. These findings reveal a novel mechanism by which PEDV hijacks host metabolism and establishes IMPDH as a promising host-directed therapeutic target for combating this economically devastating virus.

Keywords:  IMPDH; merimepodib; nucleotide biosynthesis; porcine epidemic diarrhea virus (PEDV)

DOI:  https://doi.org/10.1128/jvi.01736-25
Mol Neurobiol. 2026 Jan 04. 63(1): 341

Zika Virus Reprograms Microglial Mitochondrial Metabolism to Support Immune Activation and Viral Replication: Omega-3 DHA Counteracts Neuroinflammation and Viral Persistence.

Heloísa Antoniella Braz-de-Melo, Fernanda Gomes Lago, Rafael Corrêa, Igor de Oliveira Santos, Paula Maria Quaglio Bellozi, Raquel das Neves Almeida, Wagner Fontes, Mariana S Castro, Aline Maria Araújo Martins, Raphaela Menezes de Oliveira, Nadia Martins Serpa Rossi, Gabriel Pasquarelli-do-Nascimento, Ana Luiza Gouvea, Paulo Sousa Prado, Andreza Fabro de Bem, Sônia Nair Báo, Bergmann Morais Ribeiro, Stevens Kastrup Rehen, Thomas Christopher Rhys Williams, Gary P Kobinger, Kelly Grace Magalhães.

  Microglial cells exhibit crucial metabolic adaptations to maintain neural homeostasis. However, their dysregulated activation during infections can lead to neurotoxicity and contribute to the development of neuroinflammatory disorders. Understanding the physiological and metabolic changes of microglia during immune activation is crucial for identifying protective targets against neuroinflammation. This study investigates how the Zika virus (ZIKV) alters microglia metabolism during inflammation, highlighting cellular adaptations that sustain oxidative metabolism linked to cell survival during cellular activation and viral replication. After identifying an enriched abundance of proteins related to oxidative phosphorylation and cellular component organization in the global proteomics of mouse brains following ZIKV exposure, we investigated the relevance of these pathways during in vitro infection of human microglia. ZIKV infection led to cytoskeleton remodeling via β-tubulin reallocation, which characterized an ameboid-like phenotype. Despite the indication of a shift toward increased glycolytic activity due to decreased intracellular glucose, which suggests its consumption, and the accumulation of tricarboxylic acid cycle (TCA) intermediates, ZIKV-infected microglia exhibit enhanced respiratory capacity and an abundance of smaller-sized mitochondria in the perinuclear region. The accumulation of citrate, succinate, and malate, while maintaining mitochondrial function, suggests an important metabolic adaptation that supports biosynthetic pathways and sustains cell viability under stress. Decreased intracellular glutamate abundance supports mitochondrial oxidative metabolism. Pre-treatment with the anti-inflammatory docosahexaenoic acid (DHA) mitigates ZIKV-induced metabolic alterations by reducing pro-inflammatory markers, downregulating viral entry receptors, and lowering microglial activation and viral load. This study reveals that while ZIKV induces cell death in neuronal-like cells, the mitochondrial adaptation observed in microglial infection could be a key to maintaining cell survival throughout neuroinflammation. Our findings elucidate a novel cellular adaptation during ZIKV infection involving β-tubulin reorganization and metabolic dynamics, reflecting microglial flexibility and resistance during neuroinflammation, and demonstrating the therapeutic potential of DHA in mitigating ZIKV-induced pathology.

Keywords:  Immunometabolism; Metabolic adaptation; Mitochondrial dynamics; Neuroinflammation; Zika virus

DOI:  https://doi.org/10.1007/s12035-025-05418-y
Int J Biol Macromol. 2026 Jan 02. pii: S0141-8130(25)10578-3. [Epub ahead of print]339(Pt 2): 150021

Grass carp retinoid-related orphan receptor α (gcRORαa) promotes GCRV replication via LDLR-mediated lipid accumulation.

Yang Chen, Mu Niu Yang, Wen Qi Li, Ming Xian Chang.

  Despite the knowledge of some mechanisms by which viruses hijack host lipid metabolism to support their replication, it remains poorly understood how the nuclear receptor pathways are linked to lipid-dependent viral pathogenesis in fish. In this study, we investigated the role of nuclear receptor grass carp retinoid-related orphan receptor α (gcRORαa) in grass carp reovirus (GCRV) infection. gcRORαa enhances GCRV susceptibility in host cells and promotes formation of GCRV-infected VIBs, but knockdown helps CIK cells show anti-GCRV effects. Mechanistically, gcRORαa leads to cholesterol and triglyceride accumulation, thereby enhancing the process of lipid droplet biogenesis in infected cells. gcRORαa does these jobs by targeting the cholesterol metabolic pathway, and low-density lipoprotein receptor (LDLR) is an important downstream effector. It causes to increase LDLR transcription via promoter activation and increase LDLR protein expression, thereby facilitating uptake of cholesterol-rich low-density lipoprotein (LDL) from the external environment. By knocking down LDLR, one can stop the gcRORαa-mediated lipid build-up, LD/VIBs formation, and GCRV replication. On the other hand, silencing gcRORαa does not affect LDLR function. This indicates that gcRORαa works upstream of LDLR to fuel lipid-dependent viral replication. Through this study, a new gcRORαa-LDLR axis that links nuclear receptor signaling to lipid metabolism and GCRV pathogenesis is uncovered, thereby highlighting the importance of virus-fish host metabolic crosstalk, and providing potential therapeutic targets for antiviral intervention in aquaculture.

Keywords:  Cholesterol; GCRV; LDLR; Lipid droplet; RORαa

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.150021
bioRxiv. 2026 Jan 02. pii: 2025.12.31.697156. [Epub ahead of print]

Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.

Daniel D Carroll, Kamacay Cira, Jack Archer, Jason Shapiro, Ue-Yu Pen, David Tieri, Lucia Leonor, Neda D Roofchayee, Samantha S Yee, Marc Wahab, Igor J Koralnik, John C Alverdy, Arjun S Raman, Lavanya Visvabharathy.

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naïve individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection. We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications. This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.

DOI: https://doi.org/10.64898/2025.12.31.697156
Cells. 2025 Dec 26. pii: 47. [Epub ahead of print]15(1):

Glucose Metabolism and Innate Immune Responses in Influenza Virus Infection: Mechanistic Insights and Clinical Perspectives.

Kareem Awad, Nancy N Shahin, Tarek K Motawi, Maha Abdelhadi, Reham F Barghash, Ahmed M Awad, Laura Kakkola, Ilkka Julkunen.

  This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

Keywords:  glucose metabolism; host-pathogen interactions; immune-metabolism; influenza; kinases; therapeutic targets

DOI:  https://doi.org/10.3390/cells15010047
Sci Rep. 2026 Jan 07. 16(1): 882

Lipidomic profiling of influenza A virus production in MDCK cells towards targeted clone selection.

Jocelyn A Menard, Tilia Zinnecker, Elena Godbout, Joshua A Roberts, Rozanne Arulanandam, Andrew Chen, Anne Landry, Christopher N Boddy, Udo Reichl, Jean-Simon Diallo, Yvonne Genzel, Jeffrey C Smith.

High-yield influenza virus production is essential for efficient vaccine manufacturing to support global demands. Using Madin-Darby canine kidney (MDCK) cells to produce influenza viruses is an attractive alternative to the conventional method of manufacturing vaccines using embryonated eggs. MDCK cells exhibit heterogeneity which can impact viral yields. However, the factors driving the variation between MDCK cells are not fully understood. Utilizing an untargeted liquid chromatography-mass spectrometry lipidomic approach, we investigated two proprietary MDCK clones (C59 and C113) provided by Sartorius (Germany) that differ in biochemical and viral production properties and examined their lipid profiles and dynamics upon influenza A virus (IAV) infection between 24 and 72 h. C113, a high-yield clone, displayed elevated levels across all lipid classes, aside from ether lipids compared to C59, a clone with superior growth properties. IAV infection in clone C59 and C113 displayed key differences, specifically triacylglycerols. Analysis of progeny virions from C59 and C113 clones revealed subtle differences with a positive correlation in lipid profile (R2 = 0.77), suggesting similar lipid raft domains between clones. Overall, these findings highlight specific cellular lipid signatures associated with high-yield production and demonstrate the value of integrating lipidomics methods into biomanufacturing pipelines, providing complimentary quality assurance markers.

DOI: https://doi.org/10.1038/s41598-025-33499-1
Clin Invest Med. 2025 Dec;48(4): 3-9

Analysis of the impact of SARS-CoV-2 infection on immune function and metabolic changes in college students.

Fengzhi Li, Yijin Zan, Yukun Cao, Fan Liu, Bingxin Si, Qingling Zhang, LeLa Lin, Jing Guo, Dong Wang, Xianrong Xu.

   BACKGROUND: The long-term immune and metabolic effects of COVID-19 in vaccinated populations remain incompletely characterized. This study aimed to analyze dynamic changes in lymphocyte subpopulations (T, B, and Natural Killer [NK] cells [TBNK]) and key metabolic indicators among college students post-Omicron infection with prior vaccination.
METHODS: A prospective observational cohort of 71 male students infected with the Omicron variant of COVID-19 (Beijing, China; March-April 2022) and 18 uninfected controls was followed for 2 years. TBNK subsets and metabolic parameters (uric acid, lipid profiles, β2-microglobulin) were analyzed at 3, 6, 12, and 24 months post-infection.
RESULTS: Immunologically, total lymphocytes were elevated at 3 months when compared with controls (P = 0.0063). Total T cells declined at 6 and 12 months but rebounded by 24 months (P < 0.0001). NK cells increased until 12 months, then declined (P < 0.0001). B cells decreased persistently (P < 0.05). Metabolically, uric acid and lipid parameters (total cholesterol, LDL-C, lipoprotein [a]) showed significant fluctuations, with notable increases at 1 year post-infection (P < 0.05). β2-microglobulin levels decreased significantly over time (P < 0.0001).
CONCLUSION: Omicron infection induces immune and metabolic disturbances lasting at least 1 year, with gradual but incomplete recovery by 2 years. The interplay between immune dysregulation and metabolic alterations may contribute to the long-term health effects of COVID-19. Monitoring both lymphocyte and metabolic dynamics may guide the long-term management of post-COVID-19 sequelae.

Keywords:  COVID-19; College students; Immune function; Metabolic changes; Omicron variant; TBNK lymphocyte subsets

DOI:  https://doi.org/10.3138/CIM-2025-0009
Cell Death Discov. 2026 Jan 06.

Tetrandrine-driven autophagy suppresses SARS-CoV-2 replication by modulating cholesterol and IGF signaling pathways.

Lais de O Marchioro, Sofia De Stefanis, Beatriz G Araújo, Davide Mariotti, Ingrid K M Watanabe, Michael Stumpe, Giulia Matusali, Fabrizio Maggi, Soraya S Smaili, Jörn Dengjel, Gustavo J S Pereira, Manuela Antonioli.

SARS-CoV-2 exploits multiple host cellular processes, including autophagy, a critical intracellular degradation pathway, to facilitate viral replication and evade immune detection. Tetrandrine, a natural bis-benzylisoquinoline alkaloid derived from Stephania tetrandra, has been reported to modulate autophagy and exhibits potential antiviral properties. In this study, we investigated the effects of Tetrandrine on SARS-CoV-2 infection in human lung epithelial cells (Calu-3), with a particular focus on autophagy-related mechanisms. Our results demonstrate that Tetrandrine modulates autophagic activity in a dose-dependent manner and significantly reduces SARS-CoV-2 replication, particularly when administered prior to infection. Notably, its antiviral effect is retained in autophagy-deficient cells, indicating the involvement of autophagy-independent mechanisms. Proteomic analysis of Calu-3 cells infected with the Omicron BA.5 variant revealed that Tetrandrine regulates several host pathways implicated in viral replication, including autophagy, cholesterol metabolism, and insulin-like growth factor signaling. These findings suggest that Tetrandrine exerts multifaceted antiviral effects by targeting both autophagy-dependent and -independent cellular pathways. Collectively, our data supports the potential of Tetrandrine as a therapeutic candidate against COVID-19 and warns further evaluation in preclinical and clinical models. Data are available via ProteomeXchange with identifier PXD064448.

DOI: https://doi.org/10.1038/s41420-025-02926-7
EBioMedicine. 2026 Jan 06. pii: S2352-3964(25)00561-4. [Epub ahead of print]123 106111

Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity.

Claudio Cappadona, Valeria Rimoldi, Francesca Tettamanzi, Giulia Cardamone, Alberto Mantovani, Giulia Soldà, Elvezia Maria Paraboschi, Rosanna Asselta.

   BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in ∼200,000 COVID-19-related deaths. Unravelling host genetic factors underlying disease severity is key to understanding progression mechanisms.
METHODS: We applied multi-omics approaches to investigate genetic susceptibility to COVID-19 severity in the Italian population. We combined an exome-wide case-control study of rare germline variants (215 severe/critically ill patients vs 1755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalised patients to identify signatures associated with severe respiratory outcomes (ICU admission).
FINDINGS: Rare variant analysis revealed significant associations with genes implicated in oxidative stress and mitochondrial dysfunction, including MTERF1 (FDR = 7.69 × 10-5), TDP1 (FDR = 3.23 × 10-7), and LPO (FDR = 1.58 × 10-2). Pathway analyses confirmed enrichment in "reactive oxygen species", "oxidative phosphorylation", and "inflammatory response" pathways. Transcriptomics showed a proinflammatory profile in hospitalised patients (N = 24) and a prothrombotic signature in ICU-admitted individuals (N = 35), reflecting disease progression. Genomic and transcriptomic data integration highlighted LPO, encoding the antimicrobial enzyme lactoperoxidase, as the only gene both significantly enriched for damaging variants and upregulated in ICU-admitted cases (log2FC = 0.57, FDR = 0.028). Notably, we confirmed the genetic association with severity in independent cohorts (1873 cases vs 508,532 controls; meta-analysis p = 0.0050, OR = 3.44, 95% CI = 1.71-6.89). We propose that LPO haploinsufficiency may impair host capacity to neutralise ROS, contributing to COVID-19 progression.
INTERPRETATION: In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a candidate susceptibility gene.
FUNDING: Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.

Keywords:  COVID-19; Immune response; Lactoperoxidase; Multi-omics; Oxidative stress; Thrombosis

DOI:  https://doi.org/10.1016/j.ebiom.2025.106111