bims-mevinf 2025-07-06 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–07–06
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection.
Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.
The swine acute diarrhea syndrome coronavirus spike protein promotes syncytial formation via upregulation of cellular cholesterol synthesis.
Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.
Association between enteral essential fatty acids and plasma phospholipid essential fatty acids related immune response in critically ill adults with COVID-19: A prospective cohort study.
Time-series metabolomic profiling of SARS-CoV-2 infection: Possible prognostic biomarkers in patients in the ICU by ¹H-NMR analysis.
HSV-1 hijacks mitochondrial dynamics: potential molecular mechanisms linking viral infection to neurodegenerative disorders.
Blockade of de novo dNTP biosynthesis pathway delays HIV-1 early life cycle kinetics and dynamics.
Viral subversion of host cell Ca²⁺ signaling through STIM1-Orai1-mediated SOCE: Mechanisms and implications.

PLoS Pathog. 2025 Jul 03. 21(7): e1013293

Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection.

Lonneke V Nouwen, Esther A Zaal, Inge Buitendijk, Marleen Zwaagstra, Chiara Aloise, Arno L W van Vliet, Jelle G Schipper, Alain van Mil, Celia R Berkers, Frank J M van Kuppeveld.

Viruses, including picornaviruses, modulate cellular metabolism to generate sufficient building blocks for virus replication and dissemination. Previously, we showed that two picornaviruses, coxsackievirus B3 (CVB3) and EMCV, remodel nucleotide metabolism during infection. Here, we investigated whether this modulation is attributable to specific viral proteins. For this, we studied the modulation of metabolism by several recombinant CVB3 and EMCV viruses in HeLa cells. Using isotope tracing metabolomics with three distinct labels, 13C6-glucose or 13C5/15N2-glutamine, we reveal that the 2A protease of CVB3 and the Leader protein of EMCV inhibit de novo nucleotide synthesis. Furthermore, we show that nucleotide metabolism is also reprogrammed by CVB3 and EMCV in human induced pluripotent stem cell-derived cardiomyocytes. Our insights are important to increase understanding of picornavirus-host interactions and may lead to novel therapeutic strategies.

DOI: https://doi.org/10.1371/journal.ppat.1013293
Mol Metab. 2025 Jun 26. pii: S2212-8778(25)00101-2. [Epub ahead of print] 102194

Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.

Caroline Bartman, Shengqi Hou, Fabian Correa, Yihui Shen, Victoria da Silva-Diz, Maya Aleksandrova, Daniel Herranz, Joshua D Rabinowitz, Andrew Intlekofer.

  Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.

Keywords:  Immunometabolism; Isotope tracing; Metabolomics; Tissue metabolism; Whole-body metabolism

DOI:  https://doi.org/10.1016/j.molmet.2025.102194
mBio. 2025 Jun 30. e0097625

The swine acute diarrhea syndrome coronavirus spike protein promotes syncytial formation via upregulation of cellular cholesterol synthesis.

Dakai Liu, Miaomiao Zeng, Jiyu Zhang, Liaoyuan Zhang, Hongyan Shi, Xin Zhang, Jialin Zhang, Jianfei Chen, Zhaoyang Ji, Xiuwen Li, Gengting Gu, Tingshuai Feng, Da Shi, Dongbo Sun, Li Feng.

  Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel coronavirus that causes acute diarrhea, vomiting, and high mortality in suckling piglets. Research has demonstrated that certain viruses enhance their replication by modulating intracellular cholesterol metabolism. However, the impact of SADS-CoV infection on cellular cholesterol synthesis remains unclear. Here, we found that SADS-CoV Spike (S) protein promoted syncytium formation by positively regulating cholesterol synthesis. Specifically, the virus upregulated the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase through the inhibition of AMP-activated protein kinase (AMPK) activity. This inhibition was mediated by the activation of AKT-dependent phosphorylation of AMPKα at Ser485. Further investigation revealed that SADS-CoV S protein activated the PI3K/AKT pathway to promote cholesterol synthesis, a process that required the membrane protein integrin β1 (ITGB1). Importantly, we discovered that cholesterol facilitated cell-to-cell fusion mediated by the viral S protein, which enhanced syncytium formation. In summary, our findings demonstrate that the SADS-CoV S protein enhances cellular cholesterol accumulation by activating the PI3K/AKT/AMPK pathway through ITGB1, and that cholesterol facilitates syncytium formation mediated by the viral S protein. These insights contribute to a better understanding of SADS-CoV infection mechanisms and may inform future therapeutic strategies.
IMPORTANCE: Cholesterol, a vital component of cellular membranes, is crucial for maintaining cell structure and function. It also acts as an essential host factor for the entry, replication, and propagation of various viruses. In this study, we show that the Spike protein of swine acute diarrhea syndrome coronavirus (SADS-CoV) promotes syncytial formation by upregulating cellular cholesterol synthesis. The viral Spike protein activates the PI3K/AKT signaling pathway, leading to increased cholesterol production through the inhibition of AMP-activated protein kinase (AMPK). This upregulation of cholesterol facilitates cell-to-cell fusion, a process that enhances viral spread and pathogenesis. Moreover, we demonstrate that integrin β1 (ITGB1) acts as a critical host factor that links the viral Spike protein to the activation of the PI3K/AKT pathway. ITGB1 interacts with the S protein, playing a pivotal role in viral replication and cholesterol synthesis regulation. Our findings highlight the critical role of cholesterol in SADS-CoV infection and provide a deeper understanding of the molecular mechanisms behind viral replication. This research opens up potential therapeutic strategies targeting cholesterol metabolism to mitigate the effects of SADS-CoV and similar viral infections.

Keywords:  cholesterol; spike protein; swine acute diarrhea syndrome coronavirus; syncytia

DOI:  https://doi.org/10.1128/mbio.00976-25
Sci Adv. 2025 Jul 04. 11(27): eadu3739

Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.

Amanda L Fuchs, Bharati Singh, Jillian W Jetmore, Emily B Warren, Payal Banerjee, Jose L Marin Franco, Michael A Eckhaus, Tatiana N Tarasenko, Madeleine R Assaad, Ivan Kosik, Jonathan Yewdell, Peter J McGuire.

Mitochondrial dysfunction can trigger metabolic adaptations that resemble those induced by influenza A virus (IAV) infection. Here, we show that oxidative phosphorylation (OXPHOS) impairment, modeled by Ndufs4 deficiency, reprograms lung epithelial metabolism to promote IAV pathogenesis. In both Ndufs4 knockout (KO) mice and lung epithelial cells, OXPHOS deficiency increased glycolytic flux, diverting carbons into hexosamine and de novo sialic acid (SIA) biosynthesis pathways. This led to elevated sialylation and enhanced viral attachment. In Ndufs4 KO models, adenosine monophosphate-activated protein kinase signaling was insufficient to blunt this increased metabolic flux. IAV infection further exacerbated this metabolic vulnerability, amplifying SIA and viral burden. Pharmacologic rerouting of glucose carbons with dichloroacetate reduced sialylation, viral replication, and inflammatory responses in Ndufs4 KO models. These findings reveal that mitochondrial dysfunction enhances IAV susceptibility by disrupting energy sensing and fueling viral receptor biosynthesis, highlighting the importance of epithelial metabolism in viral pathogenesis and suggesting metabolic modulation as a potential therapeutic.

DOI: https://doi.org/10.1126/sciadv.adu3739
JPEN J Parenter Enteral Nutr. 2025 Jun 27.

Association between enteral essential fatty acids and plasma phospholipid essential fatty acids related immune response in critically ill adults with COVID-19: A prospective cohort study.

Vera C Mazurak, Irma Magaly Rivas-Serna, Sarah R Parsons, Md Monirujjaman, Krista E Maybank, Oleksa G Rewa, Andrew J Cave, Caroline Richard, M Thomas Clandinin.

   BACKGROUND: Coronavirus disease 2019 (COVID-19) is a complicated disease with widely varying outcomes. Up to 20% of unvaccinated, hospitalized patients infected with COVID-19 may die during the initial three weeks. Our research shows that COVID-19 infection results in rapid, remarkable change in the balance between essential fatty acid constituents of plasma phospholipids that are substrates for synthesis of signals that regulate immunity, inflammation, and thrombosis.
METHODS: We assessed if enteral feeding of EPA (eicosapentaenoic acid, 20:5n-3) and DHA (docosahexaenoic acid; 22:6n-3) normalizes remodeling of plasma phospholipid essential fatty acid content caused by COVID-19 viral infection and modifies immune response. Blood samples were taken on day 1 of hospital admission. From the patient record, patients were categorized into two groups based on enteral formula fed by day 5 after admission: enteral feeds that contained EPA + DHA or not. These two groups were compared at 1 week and 3 weeks postadmission for plasma phospholipid fatty acids, cytokines, and chemokines.
RESULTS: Feeding EPA + DHA increases plasma content of these fatty acids in specific species of plasma phosphatidylcholine. Change in essential fatty acid status was associated with downregulation of the inflammatory signal macrophage inflammatory protein-1β and increase in interleukin-17, monocyte chemoattractant protein (MCP)-4, macrophage-derived chemokine and thymus- and activation-regulated chemokine signals. Plasma arachidonic acid content correlated with chemoattractant protein MCP-4 during early stages of infection.
CONCLUSION: We conclude that feeding COVID-19 infected intensive care unit patients enteral formulas containing EPA and DHA may alter response to infection; however, the potential benefit to clinical outcome is not clear.

Keywords:  arachidonic acid; chemokines; cytokines; intensive care unit; lipidomics; n‐3; phosphatidylcholine; polyunsaturated fatty acids

DOI:  https://doi.org/10.1002/jpen.2783
PLoS One. 2025 ;20(7): e0327244

Time-series metabolomic profiling of SARS-CoV-2 infection: Possible prognostic biomarkers in patients in the ICU by ¹H-NMR analysis.

Emir Matpan, Ahmet Tarık Baykal, Lütfi Telci, Türker Kundak, Mustafa Serteser.

The global impact of SARS-CoV-2, which causes COVID-19, remains significant, being intensified by the emergence of variants. Comprehensive metabolomic studies aimed to elucidate the distinctive metabolic footprint of the virus. For critically ill patients with COVID-19 in the intensive care unit (ICU), longitudinal monitoring based on their prognosis is crucial to optimize treatment outcomes. This study retrospectively investigated the temporal changes in the metabolomic profiles of patients admitted to the ICU with COVID-19, who were categorized into three prognostic groups: healthy discharged (HD), polyneuropathic syndrome (PS), and Exitus. In total, 32 serum samples collected in April 2020 at regular intervals (four samples per patient) and stored at -80°C, were analyzed using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Significant (p < 0.05) prognostic changes in creatine and tyrosine levels were revealed by two-way analysis of variance (ANOVA) and ANOVA-simultaneous component analysis (ASCA). Furthermore, supervised random forest analysis demonstrated excellent group prediction with a 21.9% out-of-bag error rate based on prognosis. Specifically, creatine levels were highest in the PS group, whereas tyrosine levels were highest in the Exitus group. However, no metabolite displayed significant changes over time. In addition, metabolic pathway analysis using the Kyoto Encyclopedia of Genes and Genomes database indicated that the most significantly impacted pathway (p < 0.05) across different prognostic groups was "phenylalanine, tyrosine and tryptophan biosynthesis." This preliminary study emphasizes the need for time-series analysis of samples from unvaccinated patients with varying prognoses, providing valuable insights into the metabolic impact of COVID-19.

DOI: https://doi.org/10.1371/journal.pone.0327244
Apoptosis. 2025 Jul 01.

HSV-1 hijacks mitochondrial dynamics: potential molecular mechanisms linking viral infection to neurodegenerative disorders.

Siping Kuang, Zhiyang He, Jingjing Zhang, Shuli Li, Juntao Ding, Zhenghai Ma, Beibei Zhang.

  Herpes simplex virus type 1 (HSV-1), a neurotropic virus, hijacks the critical neuronal organelle-mitochondria-to establish lifelong latent infection and potentially accelerate neurodegenerative pathologies. Research indicates that HSV-1 infection disrupts mitochondrial dynamics, impairs its bioenergetic function, and compromises interorganellar communication. This disruption is primarily achieved through the degradation of mitochondrial DNA (mtDNA) and the functional alteration of key proteins, leading to excessive production of reactive oxygen species (ROS), intracellular calcium dysregulation, and abnormal energy metabolism. These alterations not only diminish cellular energy production and exacerbate oxidative damage but also readily trigger neuronal cell death. Crucially, the virus specifically interferes with mitochondrial-endoplasmic reticulum contact sites (MERCs) to evade immune surveillance while simultaneously promoting its own replication. In severe encephalitis, mitochondrial damage is closely associated with neuroinflammation. For Alzheimer's disease (AD), HSV-1 may synergize with amyloid-beta pathology through ROS and viral proteins (such as glycoprotein B (gB) and glycoprotein I (gI)), exacerbating disease progression. Paradoxically, HSV-1 also inhibits immediate cell death to sustain host cell survival, facilitating latent viral reactivation. Research elucidating how the virus exploits mitochondria for pathogenesis suggests that future therapeutic strategies could combine classical antiviral drugs with agents that protect mitochondrial function (e.g., antioxidants). This combined approach holds promise for combating acute infection and potentially mitigating the progression of associated neurodegenerative diseases.

Keywords:  AD; HSE; HSV-1; Immune evasion; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/s10495-025-02142-9
mBio. 2025 Jun 30. e0104725

Blockade of de novo dNTP biosynthesis pathway delays HIV-1 early life cycle kinetics and dynamics.

Mohammad Anwar Siddique, Michael D McRaven, Muhammad Shoaib Arif, Edward J Allen, Charia McKee, Shravya Honne, Tahmina Sultana, Baek Kim, Ann M Carias, João I Mamede, Thomas J Hope.

  The early events of the HIV-1 life cycle, such as reverse transcription, and capsid shedding commonly known as uncoating, are interdependent and tightly regulated, enabling HIV-1 to adapt to diverse host cells. Here, we explored how host cell dNTP pool size modulates the kinetics and dynamics of HIV-1 reverse transcription and uncoating. We optimized an easy-to-use tool to inhibit the ribonucleotide reductase (RNR) catalyzed de novo pathway of dNTP biosynthesis in CHOpgsA-745, HeLa (TZMbl), and owl monkey kidney (OMK) cells. RNR inhibitor rapidly reduced the cellular dNTP pool size, thereby restricting HIV-1 infectivity in a dose-dependent manner. This restriction was reversible upon inhibitor removal, and nucleoside supplementation partially restored infection by enhancing salvage pathways. We find that RNR inhibition slows reverse transcription kinetics and delays the initiation of uncoating in both the capsid integrity and TRIM-CypA restriction assays. Besides, the depletion of intracellular dNTP pools by RNR inhibition leads to significant reductions in both early and late HIV-1 reverse transcription products, with late-stage inhibition comparable to that observed with Nevirapine treatment. To demonstrate the impact of RNR inhibitors on capsid shedding, rather than an off-target effect, we resumed the RNR inhibition-induced delayed initiation of uncoating by reintroducing external dNTPs. This induced recommencement of rapid core integrity loss demonstrating its interplay with the progression of reverse transcription. Therefore, by inhibiting the RNR-catalyzed de novo pathway of dNTP biosynthesis, we have reduced the dNTP pool of the host cells to an extent that delays the kinetics and dynamics of HIV-1 early life events.
IMPORTANCE: Cellular dNTP pool homeostasis is maintained by the interplay between the biosynthetic (de novo and salvage) pathways and hydrolyzing networks such as SAMHD1. Inhibiting de novo pathway using RNR inhibitors reduces the host cell dNTP pool size, thereby restricting HIV-1 infectivity reversibly. Whereas the salvage pathways cannot rescue HIV-1 infectivity to the full extent without the de novo pathway. This work correlates HIV-1 infectivity with the dynamic nature of dNTP turnover due to RNR small subunit switching between RRM2 & RRM2B and the action of SAMHD1. The observed modulation of HIV-1 reverse transcription and uncoating in response to RNR inhibition demonstrates the flexibility and adaptability of the virus to replicate in hostile internal cellular environments, which attempt to starve the virus of essential metabolites such as dNTPs. These findings provide insights into how RNR inhibition may impact subsequent steps, such as nuclear localization and integration, offering a foundation for future studies.

Keywords:  HIV-1; dNTPs; de novo dNTP biosynthesis pathway; early life cycle; ribonucleotide reductase (RNR)

DOI:  https://doi.org/10.1128/mbio.01047-25
Pharmacol Res. 2025 Jul 01. pii: S1043-6618(25)00271-3. [Epub ahead of print]218 107846

Viral subversion of host cell Ca²⁺ signaling through STIM1-Orai1-mediated SOCE: Mechanisms and implications.

Qingqing Lu, Yuan Ding, Yan Zhang, Shuzhen Liu.

  Viral infection hijacks host cell physiological processes to replicate and spread, in which the calcium ion (Ca2 +) signaling pathway plays a key role in the viral life cycle. Store-operated Ca2+ entry (SOCE), as the major Ca²⁺ influx pathway, is regulated by the endoplasmic reticulum (ER) Ca2+ receptor stromal interaction molecules 1 (STIM1) and plasma membrane channel protein Orai1. Recent studies have shown that viruses disrupt intracellular Ca2+ homeostasis by regulating the STIM1-Orai1-mediated SOCE pathway, thereby promoting viral entry, replication, and pathogenicity. This review systematically summarizes the mechanism of STIM1/Orai1 in viral infection and reveals the molecular basis of the Ca2+ signaling pathway hijacked by viruses, offering a new perspective for understanding the pathogenicity of viruses. To further advance this understanding, future studies should focus on the interaction between viral proteins and STIM1-Orai1 and its downstream signaling network, and aim to develop highly selective inhibitors targeting the SOCE pathway to provide new strategies for antiviral therapy and drug research and development. Collectively, these studies not only deepen the understanding of virus-host interactions but also lay the theoretical foundation for precision medicine and antiviral therapy.

Keywords:  Ca(2+); Orai1; SOCE; STIM1; Viral infection

DOI:  https://doi.org/10.1016/j.phrs.2025.107846