bims-mevinf 2025-05-11 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–05–11
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

The impact of fatty acid synthase on HSV-1 infection dynamics.
Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection.
Biomarkers of Oxidative Stress in COVID-19 Patients.
Dexamethasone disrupts intracellular pH homeostasis to delay coronavirus infectious bronchitis virus cell entry via sodium hydrogen exchanger 3 activation.
A fijivirus capsid protein hijacks autophagy degrading an ω-3 fatty acid desaturase to suppress jasmonate-mediated antiviral defence.
Proviral insights of glycolytic enolase in Bamboo mosaic virus replication associated with chloroplasts and mitochondria.
Plasma metabolomics signatures predict COVID-19 patient outcome at ICU admission comparable to clinical scores.
Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection.
HSV-1 alters lipid metabolism and induces lipid droplet accumulation in functionally impaired mouse dendritic cells.

PLoS Pathog. 2025 May 06. 21(5): e1013068

The impact of fatty acid synthase on HSV-1 infection dynamics.

Camilla Albano, Linda Trifirò, Weronika Hewelt-Belka, Dana M Cairns, Selina Pasquero, Gloria Griffante, Francesca Gugliesi, Greta Bajetto, Dorota Garwolińska, Marika Rossi, Marta Vallino, Mario Malerba, Marco De Andrea, David L Kaplan, Valentina Dell'Oste, Matteo Biolatti.

Herpes simplex virus type-1 (HSV-1) is a widespread human pathogen that relies on host cell pathways, including those involved in metabolism to support replication. Here, we demonstrate that de novo lipogenesis is essential for HSV-1 infectivity. Specifically, HSV-1 infection upregulates fatty acid synthase (FASN) expression, accompanied by a marked increase in lipids and a differential lipid species distribution. Conversely, silencing FASN or applying FASN inhibitors (i.e., CMS121 and C75) markedly reduces the infectivity of newly released HSV-1 virions, suggesting that while initial replication remains unaffected, FASN is crucial for maintaining virion structure and facilitating entry into host cells. Additionally, we show that a source of lipid-rich external factors provided by fetal bovine serum significantly increases HSV-1 infectivity. Specifically, HSV-1 infection enhanced CD36-mediated fatty acid uptake, especially in FASN-depleted cells, compensating for reduced lipogenesis. Blocking CD36 function with SSO further decreased viral infectivity, demonstrating the critical role of lipid uptake in HSV-1 life cycle. Altogether, our findings reveal how HSV-1 manipulates lipid metabolism, offering insights into its association with chronic disease and therapeutic intervention.

DOI: https://doi.org/10.1371/journal.ppat.1013068
FASEB J. 2025 May 15. 39(9): e70600

Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection.

Jeffrey A Tomalka, Anna Owings, Michelle Galeas-Pena, Carly G K Ziegler, Tanya O Robinson, Thomas G Wichman, Hannah Laird, Haley B Williams, Neha S Ghaliwal, Steven Everman, Yousaf Zafar, Jaclyn M L Walsh, Alex K Shalek, Bruce H Horwitz, Jose Ordovas-Montanes, Sarah C Glover, Yann Gibert.

  Many questions remain unanswered regarding the implication of genetics and lipid metabolites with severe SARS-CoV-2 infections. We performed bulk RNA-seq and a total fatty acid panel analysis on PBMCs and plasma collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites using the Mann-Whitney U-test revealed that six lipid metabolites were significantly increased in COVID-19 patients, including the lipid mediators arachidonic acid (AA) and eicosapentaenoic acid (EPA), which both give rise to eicosanoids. Key lipids implicated in inflammation, including AA and EPA, along with the fatty acids DHA and DPA, were significantly and positively correlated to the WHO disease severity score. Analysis of our bulk RNA-seq dataset demonstrated distinct transcriptional profiles leading to a segregation of COVID-19 patients based on the WHO score. Ontology, KEGG, and Reactome analysis identified several key pathways and nodes that were enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling, and subsequent DNA damage pathways. EPA levels correlated with heightened cell cycling and DNA damage pathways observed in patients with a high WHO score. We studied gene expression in nasopharyngeal swabs from 58 healthy and COVID-19 participants and identified that genes implicated in eicosanoid synthesis, such as alox5, alox12, and alox15B, were specifically up-regulated in high WHO score patients in several cell types of the nasopharynx, especially goblet cells across different viral variants (Deta and Omicron). Using published nasal scRNA-seq datasets from COVID-19 patients, we evaluated the expression of genes implicated in eicosanoid synthesis, such as ALOX5, ALOX15, and ALOX15B, across nasal cell types and COVID-19 severity groups. Altogether, our study highlights the fact that the increase in specific lipids implicated in inflammation and the genes required for their synthesis correlated with the severity of the SARS-CoV-2 infection.

Keywords:  DNA damage; RNAseq; SARS‐CoV‐2; eicosanoids; fatty acid; lipidomics

DOI:  https://doi.org/10.1096/fj.202403195R
Int J Mol Sci. 2025 Apr 19. pii: 3869. [Epub ahead of print]26(8):

Biomarkers of Oxidative Stress in COVID-19 Patients.

Elitsa Pavlova, Petar Atanasov, Ivaylo Ivanov, Georgi Dyankov.

  We focused on evaluating oxidative stress as a major mechanism of cell damage in patients with COVID-19 infection by simultaneously assessing standard oxidative stress biomarkers in vivo-for the very first time in this specific combination-alongside typical clinical biomarkers of inflammation. Standard biomarkers were used to evaluate the oxidative stress status and antioxidant activity in the blood plasma of COVID-19 patients and healthy controls. These included TBARSs (Thiobarbituric Acid-Reactive Substances), SOD (Super Oxide Dismutase), CAT (catalase), GRA (glutathione reductase) activities, and AOC (antioxidant capacity). All clinical inflammation data confirmed a highly activated immune response in the tested COVID-19 patients: WBCs (white blood cells) were increased by nearly 100%, LYMs (lymphocytes) increased by ~30%, CRP (C-reactive protein) rose by over 2200%, and the ESR (erythrocyte sedimentation rate) increased by ~320% compared to established maximum control levels. The results confirmed that the infection involved a free-radical-mediated damage mechanism: TBARS levels increased almost 3-fold, the AOC decreased more than 4-fold, SOD was increased nearly 5-fold, CAT was increased by 1.4 times, and GRA was suppressed by 2.5 times. COVID-19 was associated with oxidative stress and suppressed antioxidant activity. All these changes contribute to the severity of the disease, complications, and mortality in COVID-19 patients.

Keywords:  COVID-19; biomarkers; correlation; inflammation; oxidative stress

DOI:  https://doi.org/10.3390/ijms26083869
J Virol. 2025 May 09. e0189424

Dexamethasone disrupts intracellular pH homeostasis to delay coronavirus infectious bronchitis virus cell entry via sodium hydrogen exchanger 3 activation.

Jun Dai, Yiyi Feng, Hong Long, Ying Liao, Lei Tan, Yingjie Sun, Cuiping Song, Xusheng Qiu, Chan Ding.

  Coronavirus entry into host cells enables the virus to initiate its replication cycle efficiently while evading host immune response. Cell entry is intricately associated with pH levels in the cytoplasm or endosomes. In this study, we observed that the sodium hydrogen exchanger 3 (Na+/H+ exchanger 3 or NHE3), which is strongly activated by dexamethasone (Dex) to promote cell membrane Na+/H+ exchange, was critical for cytoplasmic and endosomal acidification. Dex activates NHE3, which increases intracellular pH and blocks the initiation of coronavirus infectious bronchitis virus (IBV) negative-stranded genomic RNA synthesis. Also, Dex antiviral effects are relieved by the glucocorticoid receptor (GR) antagonist RU486 and the NHE3 selective inhibitor tenapanor. These results show that Dex antiviral effects depend on GR and NHE3 activities. Furthermore, Dex exhibits remarkable dose-dependent inhibition of IBV replication, although its antiviral effects are constrained by specific virus and cell types. To our knowledge, this is the first report to show that Dex helps suppress the entry of coronavirus IBV into cells by promoting proton leak pathways, as well as by precisely tuning luminal pH levels mediated by NHE3. Disrupted cytoplasmic pH homeostasis, triggered by Dex and NHE3, plays a crucial role in impeding coronavirus IBV replication. Therefore, cytoplasmic pH plays an essential role during IBV cell entry, probably assisting viruses at the fusion and/or uncoating stages. The strategic modulation of NHE3 activity to regulate intracellular pH could provide a compelling mechanism when developing potent anti-coronavirus drugs.IMPORTANCESince the outbreak of coronavirus disease 2019, dexamethasone (Dex) has been proven to be the first drug that can reduce the mortality rate of coronavirus patients to a certain extent, but its antiviral effect is limited and its underlying mechanism has not been fully clarified. Here, we comprehensively evaluated the effect of Dex on coronavirus infectious bronchitis virus (IBV) replication and found that the antiviral effect of Dex is achieved by regulating sodium hydrogen exchanger 3 (NHE3) activity through the influence of glucocorticoid receptor on cytoplasmic pH or endosome pH. Dex activates NHE3, leading to an increase in intracellular pH and blocking the initiation of negative-stranded genomic RNA synthesis of coronavirus IBV. In this study, we identified the mechanism by which glucocorticoids counteract coronaviruses in cell models, laying the foundation for the development of novel antiviral drugs.

Keywords:  Na+/H+exchanger 3; coronavirus; dexamethasone; infectious bronchitis virus; pH

DOI:  https://doi.org/10.1128/jvi.01894-24
Plant Biotechnol J. 2025 May 05.

A fijivirus capsid protein hijacks autophagy degrading an ω-3 fatty acid desaturase to suppress jasmonate-mediated antiviral defence.

Jianjian Liu, Xinxin Jing, Pengyue Wang, Gaohua Wang, Meirong Xiang, Pengbai Li, Hongfeng Zou, Honglian Li, Zujian Wu, Chaonan Wang, Songbai Zhang, Chao Zhang.

  Plant viruses often suppress jasmonic acid (JA)-mediated defences through disturbing JA signalling or biosynthesis pathways to benefit their own infection. Few studies have examined how the precursors of JA biosynthesis are regulated by viral infection. In this study, we demonstrate that rice black-streaked dwarf virus (RBSDV) infection inhibits the production of α-linolenic acid (C18:3), a key JA biosynthesis precursor that is catalysed by a set of fatty acid desaturases (FADs). The viral capsid protein P10 directly interacts with OsFAD7, an ω-3 fatty acid desaturase, and promotes its autophagic degradation through an ATG8-interaction motif (AIM). This disrupts JA production and weakens antiviral defence against RBSDV infection. Genetic analysis reveals that overexpression of OsFAD7 enhances JA levels and resistance to virus. But OsFAD7-mediated antiviral resistance is attenuated if OsCOI1a, a JA receptor, is silenced, indicating that the enhancement of resistance to RBSDV infection conferred by OsFAD7 depends on the JA pathway. Our findings reveal a novel viral strategy that suppresses JA biosynthesis at its metabolic source, providing insights for developing viral protection strategies and virus-resistant crops.

Keywords:  antiviral defence; autophagy; fatty acids; jasmonic acid pathway; rice viruses

DOI:  https://doi.org/10.1111/pbi.70119
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2415089122

Proviral insights of glycolytic enolase in Bamboo mosaic virus replication associated with chloroplasts and mitochondria.

Kuan-Yu Lin, Ying-Wen Huang, Liang-Yu Hou, Hsin-Chuan Chen, Yu Wu, I-Hsuan Chen, Ying-Ping Huang, Shu-Chuan Lee, Chung-Chi Hu, Ching-Hsiu Tsai, Yau-Heiu Hsu, Na-Sheng Lin.

  Diverse single-stranded RNA viruses employ different host cellular organelles or membrane systems to compartmentalize their replication intermediates and proviral factors, ensuring robust replication. Replication of Bamboo mosaic virus (BaMV), an Alphaflexiviridae family, is tightly associated with chloroplasts and dynamic cytosolic viral replication complex (VRC) clusters. BaMV VRC clusters comprise double-stranded viral RNA, BaMV replicase (RepBaMV), and mitochondrial outer membrane protein, voltage-dependent anion channel (VDAC). In this study, we demonstrate that host glycolytic enolase (ENO) binds to untranslated regions of BaMV RNA independently of ENO hydrolytic activity. However, the structural integrity of ENO is essential for its direct interaction with RepBaMV, and its positive regulating role in BaMV replication and the size of BaMV VRC clusters. Additionally, ENO, pyruvate kinase (PYK), and VDAC colocalize within cytosolic BaMV VRC clusters embedded in the convoluted endomembrane reticulum (ER) along with ER-targeted viral movement proteins under BaMV infection. This association suggests that the ENO-PYK-VDAC metabolon, with ENO serving as a scaffold to link chloroplasts and mitochondria, may play a pivotal role in BaMV robust replication. Collectively, our findings offer significant insights into how glycolytic ENO acts in BaMV replication.

Keywords:  Bamboo mosaic virus; chloroplast-mitochondria association; enolase; viral replication complex

DOI:  https://doi.org/10.1073/pnas.2415089122
Sci Rep. 2025 May 03. 15(1): 15498

Plasma metabolomics signatures predict COVID-19 patient outcome at ICU admission comparable to clinical scores.

Sigurður T Karvelsson, Emmanuel Besnier, Arnar Ingi Vilhjálmsson, Camille Molkhou, Freyr Jóhannsson, Perrine Lepretre, Étienne Ljóni Poisson, Fabienne Tamion, Jérémy Bellien, Óttar Rolfsson, Adrián López García de Lomana, Thomas Duflot.

  SARS-CoV-2 significantly impacts the human metabolome. This study aims to evaluate the predictive capability of a comprehensive module clustering approach in plasma metabolomics for identifying the risk of critical complications in COVID-19 patients admitted to intensive care units (ICUs). We conducted a prospective monocenter study, gathering blood samples within 24 h of ICU admission, alongside clinical, biological, and demographic patient characteristics. Subsequently, we quantified patients' plasma metabolome using a comprehensive untargeted metabolomics approach. First, we stratified patients based on a composite outcome score indicating critical status. Analysis of potential predictors revealed that older patients with higher severity scores and pronounced alterations in key biological parameters are more likely to experience critical complications. Next, we identified 6,667 metabolic features clustered into 57 annotated metabolic modules across all patients by employing an integrative metabolomics approach. Furthermore, we identified the most differentially expressed metabolic modules related to patients' outcomes. Moreover, we defined the top five most predictive metabolites of critical status: homoserine, urobilinogen, methionine, xanthine and pipecolic acid. These five predictors alone demonstrated similar or superior performance compared to clinical and demographic variables in predicting patients' outcomes. This innovative metabolic module inference approach offers a valuable framework for identifying patients prone to complications upon ICU admission for COVID-19. Its potential applications extend to enhancing patient management across diverse clinical settings.

Keywords:  COVID-19; Critical care; Metabolomics; Network clustering; Prediction

DOI:  https://doi.org/10.1038/s41598-025-00373-z
medRxiv. 2025 Apr 17. pii: 2025.04.16.25325949. [Epub ahead of print]

Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection.

Silvia Lucena Lage, Katherine Bricker-Holt, Joseph M Rocco, Adam Rupert, Frank X Donovan, Yevgeniya A Abramzon, Settara C Chandrasekharappa, Colton McNinch, Logan Cook, Eduardo Pinheiro Amaral, Gabriel Rosenfeld, Thomas Dalhuisen, Avery Eun, Rebecca Hoh, Emily Fehrman, Jeffrey N Martin, Steven G Deeks, Timothy J Henrich, Michael J Peluso, Irini Sereti.

  SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Keywords:  COVID-19; Long COVID; immunosenescence; inflammation; metabolism; post-acute sequelae of SARS-CoV-2

DOI:  https://doi.org/10.1101/2025.04.16.25325949
iScience. 2025 May 16. 28(5): 112441

HSV-1 alters lipid metabolism and induces lipid droplet accumulation in functionally impaired mouse dendritic cells.

Mónica A Farías, Felipe A Cancino, Areli J Navarro, Luisa F Duarte, Abel A Soto, Eduardo I Tognarelli, Maximiliano J Ramm, Bárbara N Alarcón-Zapata, José Cordero, Sergio San Martín, Cristian Agurto-Muñoz, Angello Retamal-Díaz, Claudia A Riedel, Nelson P Barrera, Luis Bustamante, Susan M Bueno, Alexis M Kalergis, Pablo A González.

  Herpes simplex virus type 1 (HSV-1) significantly impairs dendritic cell (DC) function, ultimately eliciting the death of these cells. Here, we sought to assess whether HSV-1 modulates lipid metabolism in mouse DCs as a mechanism of immune evasion. For this, we performed RT-qPCR gene arrays with ingenuity pathway analysis (IPA), RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA), confocal microscopy, transmission electron microscopy, ultra-high-performance liquid chromatography-quadrupole time-of-flight (UHPLC-QTOF) analysis, pharmacological inhibition of eight lipid-metabolism-related enzymes in HSV-1-infected DCs, co-cultures between virus-specific transgenic CD4+ and CD8+ T cells and HSV-1-infected DCs, and in vivo assays with mice. We found that HSV-1 significantly alters lipid metabolism in DCs and induces lipid droplet (LD) accumulation in these cells. Pharmacological inhibition of two particular lipid metabolism enzymes was found to partially restore DC function. Overall, these results suggest that lipid metabolism plays an important role in the impairment of DC function by HSV-1.

Keywords:  Biochemistry; Biological sciences; Cell biology; Immunology; Microbiology; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2025.112441