bims-mevinf 2025-05-25 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–05–25
sixteen papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Classical swine fever virus utilizes stearoyl-CoA desaturase 1-mediated lipid metabolism to facilitate viral replication.
Chikungunya virus infection under high glucose environment reverts insulin unresponsiveness and promotes cellular metabolic shift to increase anaplerosis and virion production.
The PERK-eIF2α Pathway of the Unfolded Protein Response Inhibits White Spot Syndrome Virus Infection by Attenuating Global Protein Translation.
Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.
Co-opted ATG2 lipid transfer protein delivers phospholipids for biogenesis of viral replication organelles.
Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses.
Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.
Dynamic Alterations of the Intestinal Microbiome and Metabolome During Transmissible Gastroenteritis Virus Infection in Weaned Pigs.
Metformin as antiviral therapy protects hyperglycemic and diabetic patients.
PINK1/PARKIN-mediated mitophagy inhibits the interferon response and promotes viral replication during Pseudorabies virus infection.
Modulating Fatty Acid Metabolism to Counteract Cucumber Green Mottle Mosaic Virus Infection in Cucumber.
Metabolic signature of COVID-19 progression: potential prognostic markers for severity and outcome.
Plasma lipid metabolites differentiate metabolic from viral chronic liver disease.
HBV-driven host chromatin accessibility changes affect liver metabolic pathways, iron homeostasis and promote a preneoplastic phenotype.
Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.
Fatty acid desaturases link cell metabolism pathways to promote proliferation of Epstein-Barr virus-infected B cells.

J Virol. 2025 May 19. e0055125

Classical swine fever virus utilizes stearoyl-CoA desaturase 1-mediated lipid metabolism to facilitate viral replication.

Ji-Shan Bai, Lin-Ke Zou, Ya-Yun Liu, Lin-Han Zhong, Jing Chen, Jin-Xia Chen, Bing-Qian Zhao, Rong-Chao Liu, Bo-Tao Sun, Bin Zhou.

  Viral infections can significantly alter cellular lipid metabolism by modulating key rate-limiting enzymes, including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and acetyl-CoA carboxylase (ACC). Our previous study revealed the pivotal role of FASN in lipid droplet (LD) synthesis and the promotion of classical swine fever virus (CSFV) replication. However, the roles of the other two key enzymes in CSFV infection remain unexplored. In this study, we screened a library of 96 lipid metabolism-targeted compounds and identified an antiviral inhibitor of SCD1, a rate-limiting enzyme in monounsaturated fatty acid synthesis, that inhibits CSFV replication. Suppressing SCD1 activity through inhibitors or small interfering RNA knockdown reduces CSFV proliferation. However, this suppression is reversed by adding SCD1 active products (oleic acid/palmitoleic acid [OA/PA]), highlighting the essential role of SCD1 in CSFV proliferation. Mechanistically, CSFV non-structural protein p7 interacts with SCD1 and recruits it to the viral replication complex (VRC) during infection. Importantly, CSFV infection activates the endoplasmic reticulum stress pathway IRE1α/XBP1, which positively regulates SCD1 expression, leading to increased production of triglyceride (TG) and LDs and subsequently enhancing CSFV replication. In summary, our study elucidates the critical role of SCD1 in the CSFV life cycle and highlights its potential as an antiviral target for developing new therapies against Flaviviridae.IMPORTANCEUnderstanding the virus's pathogenesis within the host is essential for advancing antiviral therapeutics and vaccine development. Previous studies have demonstrated that classical swine fever virus (CSFV) leverages host lipid metabolic rate-limiting enzymes, such as fatty acid synthase (FASN), to support viral replication. This study identified stearoyl-CoA desaturase 1 (SCD1), a key enzyme in monounsaturated fatty acid biosynthesis, as a novel regulator of CSFV replication. Mechanistically, the viral non-structural protein p7 mediates the recruitment of SCD1 to the endoplasmic reticulum (ER), facilitating the formation of viral replication complexes (VRCs). Additionally, our findings showed that viral infection activated the ER stress pathway IRE1α/XBP1, which upregulated SCD1 expression and promoted the synthesis of triglycerides (TG) and lipid droplets (LDs). This study provides insights into the metabolic reprogramming triggered by viral infection to support replication and underscores the intricate crosstalk between ER stress and lipid metabolism during CSFV infection. These findings have significant implications for identifying novel antiviral targets against CSFV.

Keywords:  IRE1α/XBP1; classical swine fever virus (CSFV); lipid metabolism; stearoyl-CoA desaturase 1 (SCD1)

DOI:  https://doi.org/10.1128/jvi.00551-25
Life Sci. 2025 May 20. pii: S0024-3205(25)00364-9. [Epub ahead of print] 123729

Chikungunya virus infection under high glucose environment reverts insulin unresponsiveness and promotes cellular metabolic shift to increase anaplerosis and virion production.

Bia Francis Rajsfus, José Xavier do Nascimento Júnior, Marina Santos Chichierchio, Adriane Regina Todeschini, Isadora de Araújo Oliveira, Fernando de Souza Borges, Shana Priscila Barroso, Ronaldo Mohana-Borges, Juliana Camacho Pereira, Patrícia Zancan, Diego Allonso.

   AIMS: Chikungunya virus (CHIKV) is a medically significant arbovirus responsible for Chikungunya fever (CHIKF), a debilitating disease marked by persistent joint and muscle pain. The most severe outcomes of CHIKF, including mortality, are frequently observed in individuals with comorbidities diabetes mellitus (DM). This study aimed to investigate how varying glucose concentrations influence CHIKV infection.
MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were cultured in normal glucose (NG - 5.5 mM glucose) or high glucose (HG - 25 mM glucose) to mimic normoglycemia and hyperglycemia conditions. Cells were infected with CHIKV and changes in host glucose metabolism were evaluated. Metabolic flux, viral replication, and cellular insulin sensitivity were assessed through biochemical, molecular analyses and metabolomics.
KEY FINDINGS: CHIKV infection modulates host cell metabolism in a glucose-dependent manner. Under NG conditions, the virus regulates glucose metabolism to support replication and virion production. In contrast, HG environments enhance viral replication, exploiting the altered metabolic landscape. Notably, CHIKV restores insulin sensitivity in HG conditions, leading to increased glucose uptake. It also promotes anaplerotic reactions by diverting tricarboxylic acid (TCA) cycle intermediates toward amino acid synthesis and upregulates glycolytic flux into the hexosamine biosynthesis pathway (HBP).
SIGNIFICANCE: These findings provide mechanistic insight into how hyperglycemia associated with DM can exacerbate CHIKV pathogenesis. The virus's ability to hijack and redirect host metabolic processes in high glucose environments may underline the worsened disease severity observed in diabetic patients. Understanding these interactions could inform targeted therapeutic strategies for managing CHIKF in individuals with metabolic comorbidities.

Keywords:  Anaplerosis; Chikungunya fever; Chikungunya virus; Diabetes; Glucose metabolismo; Hyperglycemia

DOI:  https://doi.org/10.1016/j.lfs.2025.123729
Fish Shellfish Immunol. 2025 May 21. pii: S1050-4648(25)00330-4. [Epub ahead of print] 110441

The PERK-eIF2α Pathway of the Unfolded Protein Response Inhibits White Spot Syndrome Virus Infection by Attenuating Global Protein Translation.

Chuang Cui, Hao Liu, Yun-Fei Zhang, Ling-Ke Liu, Hai-Peng Liu.

  As obligate intracellular pathogens, viruses rely on the endoplasmic reticulum (ER) of host cells for viral protein synthesis and processing, leading to increased ER loading, which in turn triggers ER stress and activates the unfolded protein response (UPR). And this process is intricately linked to both viral infection and the host's immune response. White spot syndrome virus (WSSV) is one of the most detrimental viral pathogens affecting farmed crustaceans such as shrimp and crayfish, but the interaction between WSSV-induced ER stress and viral infection has not been comprehensively investigated. Here, we demonstrated that WSSV infection activated all three UPR pathways, including IRE1 pathway, ATF6 pathway and PERK-eIF2α pathway in crayfish hematopoietic tissue cells. In contrast to the promoted WSSV infection by IRE1 pathway and ATF6 pathway, the activated PERK-eIF2α pathway exhibited an inhibitory effect on viral infection, which was achieved via attenuation of global protein translation of host cells mediated by phosphorylation of eIF2α. Whereas, the continuous expression of WSSV proteins appeared to bypass this translational repression. Collectively, these results emphasized the key role of the PERK-eIF2α pathway, activated by WSSV-induced ER stress, in regulating viral infection, which might constitute an important aspect of the host cell's immune response to viral infection.

Keywords:  Antiviral immunity; Endoplasmic reticulum stress; Translation inhibition; Unfolded protein response; White spot syndrome virus

DOI:  https://doi.org/10.1016/j.fsi.2025.110441
PLoS Pathog. 2025 May 19. 21(5): e1013164

Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.

Ragini Agrawal, Virender Kumar Pal, Suhas K S, Gopika Jayan Menon, Inder Raj Singh, Nitish Malhotra, Naren C S, Kailash Ganesh, Raju S Rajmani, Aswin Sai Narain Seshasayee, Nagasuma Chandra, Manjunath B Joshi, Amit Singh.

Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.

DOI: https://doi.org/10.1371/journal.ppat.1013164
Autophagy Rep. 2024 ;3(1): 2426437

Co-opted ATG2 lipid transfer protein delivers phospholipids for biogenesis of viral replication organelles.

Yuanrong Kang, Judit Pogany, Peter D Nagy.

Positive-strand RNA viruses, which are important pathogens of humans, animals and plants, subvert cellular membranes and induce de novo membrane proliferation to generate viral replication organelles (VROs) that support virus replication. Tomato bushy stunt virus (TBSV), an extensively-studied plant virus replicating in yeast model host and plants, hijacks ATG2 (autophagy-related 2), a lipid transfer protein (LTP) that transports lipids between adjacent organelles at membrane contact sites, for the biogenesis of their membranous VROs. Subversion of ATG2 by TBSV is important to enrich VRO membranes with phosphatidylethanolamine (PE), phosphatidylserine (PS) and the phosphoinositide phosphatidylinositol-3-phosphate [PI(3)P], which are all required for viral replication. TBSV replication protein directly interacts with ATG2 leading to recruitment to VRO membranes independently of the autophagy machinery.

DOI: https://doi.org/10.1080/27694127.2024.2426437
Commun Biol. 2025 May 23. 8(1): 791

Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses.

Alina Renz, Mirjam Hohner, Raphaël Jami, Maximilian Breitenbach, Jonathan Josephs-Spaulding, Johanna Dürrwald, Lena Best, Victoria Dulière, Chloé Mialon, Stefanie M Bader, Georgios Marinos, Nantia Leonidou, Filipe Cabreiro, Marc Pellegrini, Marcel Doerflinger, Manuel Rosa-Calatrava, Andrés Pizzorno, Andreas Dräger, Michael Schindler, Christoph Kaleta.

The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A virus with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

DOI: https://doi.org/10.1038/s42003-025-08148-y
FASEB J. 2025 May 31. 39(10): e70659

Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.

Xiaoyan Tian, Meng Yuan, Linrun Li, Deyan Chen, Bingxin Liu, Xue Zou, Miao He, Zhiwei Wu.

  Enterovirus 71 (EV71) infection poses a global public health challenge, especially in infants and young children, with severe cases leading to fatal consequences. EV71 infection modulates various biological processes of the host and evades host immunity through multiple mechanisms. The balance of mitochondrial dynamics is important for cellular homeostasis. However, the mechanisms underlying EV71-induced cellular damage via mitophagy remain unclear. In the current study, we showed that EV71 infection significantly reduced the total and mitochondrial ATP contents in cells, as well as the expression of mitochondrial proteins TOM20 and TIM23. Then, EV71 infection increased the protein levels of PINK1, Parkin, and LC3B, suggesting that EV71 infection triggers the mitophagy. Silencing PINK1 caused a significant reduction in viral replication, while overexpressing Parkin promoted the replication of EV71. Moreover, CsA treatment, as a mitophagy inhibitor, alleviated pathological damage and suppressed the replication of EV71 in vivo. Mechanistic study showed that silencing PINK1 inhibited the cleavage of MAVS by EV71, while overexpressing Parkin enhanced the cleavage of MAVS by EV71, suggesting that PINK1-mediated mitophagy was involved in regulating innate immunity. Furthermore, we found that EV71 infection promoted the release of mitochondria carrying EV71 virions into the extracellular environment, which mediated infection of other cells, thus facilitating virus spreading. In addition, we also demonstrated that the extracellular mitochondria induced the degradation of MAVS and mitophagy promoted the release of mitochondria in EV71-infected HeLa cells. In conclusion, these findings suggest that EV71 infection induces PINK1-mediated mitophagy, which inhibits innate immunity and facilitates virus replication.

Keywords:  EV71; PINK1; Parkin; extracellular mitochondria; mitophagy

DOI:  https://doi.org/10.1096/fj.202403315R
Microb Pathog. 2025 May 16. pii: S0882-4010(25)00430-9. [Epub ahead of print] 107705

Dynamic Alterations of the Intestinal Microbiome and Metabolome During Transmissible Gastroenteritis Virus Infection in Weaned Pigs.

Ya-Mei Chen, Chia-An Yeh, Wei-Hao Lin, Chao-Nan Lin, Ming-Tang Chiou.

  Transmissible gastroenteritis virus (TGEV) infection induces diarrhea in piglets by targeting the small intestine, especially the jejunum and ileum. However, dynamic changes in the gut microbiota and metabolome during TGEV infection remain unclear. This study investigated these alterations and their association with intestinal damage in weaned pigs during early TGEV infection. Thirty 4-week-old pigs were allocated randomly into TGEV-inoculated and mock groups. On days 3, 5, and 7 postinoculation, intestinal tissue and fecal samples were collected. Full-length 16S rRNA sequencing and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC‒MS/MS) were employed to analyze microbiota composition and nontargeted metabolites. TGEV infection resulted in reduced villous height-to-crypt depth (VH:CD) ratios (P < 0.01) and significantly altered microbial diversity (P = 0.0091 in jejunum) and composition (P = 0.001). Notably, infected pigs showed increased abundances of Lactobacillus and Limosilactobacillus species. The VH:CD ratio correlated with the overall taxonomic composition in both the jejunum and ileum (r = 0.4, P < 0.001) and was positively associated with microbial functions such as aerobic chemoheterotrophy and chitinolysis in the jejunum. Fecal metabolomics revealed 1,815 and 892 differentially expressed metabolites in the jejunum and ileum, respectively, including amino acids, fatty acids, and intermediates of energy metabolism. Integrated analysis revealed that Lactobacillus amylovorus DSM20531 was positively correlated with linoleic acid, L-tyrosine, and citric acid, whereas Lactococcus lactis showed a negative correlation with isocitric acid and glutamine. This study enhances our understanding of the pathogenesis of TGEV and provides potential microbial and metabolic biomarkers for future diagnostic and preventive strategies.

Keywords:  gut microbiota; metabolome; swine coronavirus; transmissible gastroenteritis virus; weaned pigs

DOI:  https://doi.org/10.1016/j.micpath.2025.107705
mBio. 2025 May 20. e0063425

Metformin as antiviral therapy protects hyperglycemic and diabetic patients.

Xi Wang, Xiaojie Zheng, Honghan Ge, Ning Cui, Ling Lin, Ming Yue, Chuanlong Zhu, Qi Zhou, Peixin Song, Xing Shang, Rui Wang, Zhen Wang, Zhiyou Wang, Yunfa Zhang, Xiaohong Yin, Linsheng Yang, Hong Su, Hao Li, Wei Liu.

  Viral infections disrupt glucose metabolism; however, their impact on disease prognosis in highly pathogenic viruses remains largely unknown. There is an additional need to investigate the antiviral mechanisms of glucose-lowering therapeutics. Here, our multicenter clinical study shows that hyperglycemia and pre-existing diabetes are independent risk factors for mortality in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging and highly pathogenic bunyavirus. SFTSV infection triggers gluconeogenesis, which, in turn, inhibits AMPK activity and subsequent interferon I (IFN-I) responses, thereby facilitating viral replication. In vitro and animal studies further reveal that metformin inhibits SFTSV replication by suppressing autophagy through the AMPK-mTOR pathway, contributing to protection against lethal SFTSV infection in mice. Importantly, our large cohort study demonstrates that metformin reduces viremia and SFTSV-related mortality in patients with hyperglycemia or pre-existing diabetes, contrasting with the disadvantageous effect of insulin. These findings highlight the promising therapeutic potential of metformin in treating viral infections, particularly among individuals with hyperglycemia or diabetes.
IMPORTANCE: Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes severe hemorrhagic fever with a high mortality rate. Previous studies have shown metabolic disturbances, particularly hyperglycemia, in SFTSV-infected individuals. However, the mechanism underlying this metabolic derangement remains unclear, and further investigation is needed to determine whether glucose-lowering therapeutics could be beneficial for SFTSV-infected patients. In this study, our multicenter clinical data show that hyperglycemia and pre-existing diabetes are independent risk factors for mortality in patients with SFTSV infection. Furthermore, we observed that SFTSV infection triggers gluconeogenesis, which promotes viral replication through the regulation of the AMPK-IFN-I signaling pathway. Notably, metformin significantly reduces viremia and SFTSV-related mortality in patients with hyperglycemia or pre-existing diabetes, attributed to its inhibitory effect on autophagy through the AMPK-mTOR pathway. Therefore, our study uncovers the interaction between SFTSV infection and glucose metabolic disorder and highlights the promising therapeutic potential of metformin for treating SFTSV infection.

Keywords:  antiviral therapy; diabetes; hyperglycemia; metformin; severe fever with thrombocytopenia syndrome virus

DOI:  https://doi.org/10.1128/mbio.00634-25
Autophagy Rep. 2024 ;3(1): 2422214

PINK1/PARKIN-mediated mitophagy inhibits the interferon response and promotes viral replication during Pseudorabies virus infection.

Yuan Zhao, Zhenbang Zhu, Wenqiang Wang, Zhendong Zhang, Wei Wen, Xiangdong Li.

  Pseudorabies virus (PRV) poses a significant threat to the global swine industry, characterized by high morbidity and a range of sequelae in infected pigs. Mitochondria serve as a crucial platform for innate immunity, playing a pivotal role in a wide array of antiviral responses. In our recent study, we revealed that PRV infection induces mitochondrial disruption, which in turn triggers PINK1/PARKIN-mediated mitophagy. We also show that this process leads to the degradation of the mitochondrial antiviral signaling protein (MAVS) and the inhibition of antiviral interferon production and signaling, ultimately facilitating viral replication.

Keywords:  Interferons; MAVS; Pseudorabies virus; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/27694127.2024.2422214
Plant Cell Physiol. 2025 May 21. pii: pcaf053. [Epub ahead of print]

Modulating Fatty Acid Metabolism to Counteract Cucumber Green Mottle Mosaic Virus Infection in Cucumber.

Tong Jiang, Deping Ding, Sihan Zhen, Xinye Su, Yuhui Wang, Jiashuo Liu, Xinyue Wang, Hengyun Mi, Tianwen Hao, Wenjing Chen, Chengliang Li, Shuqi Pang, Chenglong Fu, Yueying Sun, Mansour Ghorbanpour, Shuo Miao.

  As plants often alter their metabolism in response to viral infections, the mechanisms involved in this process remain a research hotspot. Here, we examined the leaf fatty acid (FA) content in cucumber plants and revealed significant changes in the composition of FAs before and after severe cucumber green mottle mosaic virus (CGMMV) infection. Before severe CGMMV infection, saturated FAs accumulated, whereas unsaturated FAs decreased. Meanwhile, the opposite was observed after CGMMV infection. The expression and localization of the stearoyl-acyl-carrier-protein desaturase 2 (CsSSI2), which is responsible for FA desaturation, were modulated upon CGMMV infection. The accumulation of both saturated FA substrates and unsaturated FA products resulting from CsSSI2 activity, as well as silencing of the CsSSI2 gene, hindered CGMMV infection. Furthermore, CsSSI2-mediated changes in FA composition affected the balance between jasmonic acid (JA) and salicylic acid (SA), favoring a shift from SA to JA biosynthesis during severe CGMMV infection, thereby contributing to the inhibition of CGMMV infection and its physical transmission. Overall, our study sheds novel insights into the mechanism whereby FA metabolism in cucumber plants adapts to counteract viral infection, expanding our understanding of plant-virus interactions and suggesting potential strategies for enhancing crop resistance to viral diseases.

Keywords:  cucumber green mottle mosaic virus; fatty acid metabolism; hormone; plant-virus interactions

DOI:  https://doi.org/10.1093/pcp/pcaf053
Metabolomics. 2025 May 21. 21(3): 70

Metabolic signature of COVID-19 progression: potential prognostic markers for severity and outcome.

Hien Thi Thu Nguyen, Malene Pontoppidan Stoico, Vang Quy Le, Jakob Holm Dalsgaard Thomsen, Kasper Bygum Krarup, Karoline Assifuah Kristjansen, Inge Søkilde Pedersen, Henrik Bygum Krarup.

   INTRODUCTION: There are significant challenges remain in accurately categorizing the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients.
OBJECTIVES: We used an untargeted 1H NMR-based metabolomics to assess the metabolomic changes in serum samples from a Danish cohort of 106 COVID-19-infected patients with mild to fatal disease courses and from patients with fatal outcomes from other diseases.
METHODS: In total, 240 serum samples were used for this study. We used the data for multiple analyses (1) to construct a predictive model for disease severity and outcome, (2) to identify prognostic markers for subsequent disease severity and outcome, and (3) to understand the disease consequences in the metabolome and how recovery or death is reflected in the altered biological pathways.
RESULTS: Our results revealed distinct alterations in the serum metabolome that could differentiate patients with COVID-19 by severity (mild or severe) or outcome (death or survival). Using receiver operating characteristic (ROC) curve analysis and four machine learning algorithms (random forest, linear support vector machine, PLS-DA, and logistic regression), we identified two biomarker sets with relevant biological functions that predict subsequent disease severity and patient outcome. The range of these severity-associated biomarkers was equally broad and included inflammatory markers, amino acids, fluid balance, ketone bodies, glycolysis-related metabolites, lipoprotein particles, and fatty acid levels.
CONCLUSIONS: Our data suggest the potential benefits of broader testing of these metabolites from newly diagnosed patients to predict which COVID-19 patients will progress to severe disease and which patients will manifest severe symptoms to minimize mortality.

Keywords:  COVID-19; Metabolomics; NMR; Prognostic markers; Severity and outcome prediction models

DOI:  https://doi.org/10.1007/s11306-025-02264-w
J Infect Dis. 2025 May 23. pii: jiaf270. [Epub ahead of print]

Plasma lipid metabolites differentiate metabolic from viral chronic liver disease.

Kara Wegermann, Joseph E Lucas, Laura Dubois, Rebecca Mangus, Zhong Li, Cynthia A Moylan, Keyur Patel, Susanna Naggie.

   BACKGROUND AND AIM: Lipid metabolism is altered in human immunodeficiency virus (HIV) infection and chronic liver diseases, but common and unique pathways have not been elucidated, limiting prevention and treatment strategies. The aim of this study was to discover lipid metabolite signatures for persons with HIV (PWH), PWH with HCV coinfection (PWH-HCV), and individuals with metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD, MASH).
METHODS: Plasma metabolite profiling was performed in adult participants in five cohorts from a single center: PWH (N = 50), PWH-HCV (N = 50), HIV-negative biopsy-proven MASLD (N = 46) and MASH (N = 50), and controls without HIV or chronic liver disease (N = 29). Plasma metabolites were assessed using Biocrates Q500, Bile Acid, and oxylipin assays. Latent factor analysis along with unadjusted and adjusted logistic regression models were performed. Significance was defined as p-value < 0.05 and false discovery rate (FDR) < 0.10.
RESULTS: Compared to controls, 457 of 816 measured metabolites were detected at different levels in PWH, 352 in PWH-HCV, 466 in MASLD, and 487 in MASH. Triglycerides and oxylipins were increased across disease states, but to a higher degree in PWH. PWH-HCV had a distinct metabolite signature with decreased ceramides and sphingomyelins. Levels of bile acid, amino acid, and fatty acid metabolites also differentiated cohorts.
CONCLUSIONS: Lipid metabolites demonstrated pathways common to, and unique to, HIV, HCV, and MASLD. Further studies will hopefully reveal the pathogenic role of these metabolites in liver disease severity, particularly in PWH with steatotic liver disease.

Keywords:  Biomarker; HIV; MASLD; Metabolite; Steatosis

DOI:  https://doi.org/10.1093/infdis/jiaf270
J Exp Clin Cancer Res. 2025 May 16. 44(1): 146

HBV-driven host chromatin accessibility changes affect liver metabolic pathways, iron homeostasis and promote a preneoplastic phenotype.

Vincenzo Alfano, Giuseppe Rubens Pascucci, Giacomo Corleone, Massimiliano Cocca, Francesca De Nicola, Océane Floriot, Alexia Paturel, Francesca Casuscelli Di Tocco, Claude Caron de Fromentel, Philippe Merle, Michel Rivoire, Massimo Levrero, Francesca Guerrieri.

   BACKROUND AND AIMS: Complex host-virus interactions account for adaptive and innate immunity dysfunctions and viral cccDNA mini-chromosome persistence, key features of HBV chronicity and challenges for HBV cure. The extent of HBV direct impact on liver transcriptome remains controversial. Transcriptional activation in eukaryotic cells is tightly linked with disruption of nucleosome organization at accessible genomic sites of remodeled chromatin. We sought to investigate the impact of HBV on chromatin accessibility and transcription.
METHODS: We used ATAC-seq (Assay for Transposase Accessible Chromatin followed by high throughput sequencing) to detect early changes in chromatin accessibility coupled with RNA-seq in HBV-infected Primary Human Hepatocytes (PHHs).
RESULTS: An increasing number of genomic sites change their nucleosome organization over time after HBV infection, with a prevalent, but not exclusive, reduction of chromatin accessibility at specific sites that is partially prevented by inhibiting HBV transcription and replication. ATAC-seq and RNA-seq integration showed that HBV infection impacts on liver fatty acids, bile acids, iron metabolism and liver cancer pathways. The upregulation of iron uptake genes leads to a significant increase of iron content in HBV-infected PHHs whereas iron chelation inhibits cccDNA transcription and viral replication. The chromatin accessibility and transcriptional changes imposed by HBV early after infection persist, as an epigenetic scar, in chronic HBV (CHB) patients and in HBV-related HCCs. These changes are to a large extent independent from viral replication levels and disease activity.
CONCLUSIONS: Altogether our results show that HBV infection impacts on host cell chromatin landscape and specific transcriptional programs including liver metabolism and liver cancer pathways. Re-wiring of iron metabolism boosts viral replication early after infection. The modulation of genes involved in cancer-related pathways may favor the development or the selection of a pro-neoplastic phenotype and persists in HBV-related HCCs.

Keywords:  ATAC-seq; Chromatin remodeling; HBV-related HCC ; Iron uptake; RNA-seq

DOI:  https://doi.org/10.1186/s13046-025-03414-7
Nat Microbiol. 2025 May 22.

Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.

Qing Zhu, Robert McElroy, Janvhi Suresh Machhar, Joel Cassel, Zihan Zheng, Behzad Mansoori, Hongrui Guo, Sen Guo, Christian Pangilinan, Jinghui Liang, Dongliang Shen, Lu Zhang, Qin Liu, Andrew V Kossenkov, Dario C Altieri, Paul M Lieberman, Shou-Jiang Gao, Pinghui Feng, Maureen E Murphy, Jikui Song, Joseph M Salvino, Qiming Liang, Jae U Jung, Chengyu Liang.

Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41564-025-02018-3
PLoS Pathog. 2025 May 22. 21(5): e1012685

Fatty acid desaturases link cell metabolism pathways to promote proliferation of Epstein-Barr virus-infected B cells.

Emmanuela N Bonglack, Kaeden K Hill, Ashley P Barry, Alexandria Bartlett, Pol Castellano-Escuder, Matthew D Hirschey, Micah A Luftig.

Epstein-Barr virus (EBV) is a gamma herpesvirus that infects up to 95% of the human population by adulthood, typically remaining latent in the host memory B cell pool. In immunocompromised individuals, EBV can drive the transformation and rapid proliferation of infected B cells, ultimately resulting in neoplasia. The same transformation process can be induced in vitro, with EBV-infected peripheral blood B cells forming immortalized lymphoblastoid cell lines (LCLs) within weeks. In this study, we found that the fatty acid desaturases stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) are upregulated by EBV and crucial for EBV-induced B cell proliferation. We show that pharmacological and genetic inhibition of both SCD1 and FADS2 results in a significantly greater reduction in proliferation and cell cycle arrest, compared to perturbing either enzyme individually. Additionally, we found that inhibiting either SCD1 or FADS2 alone hypersensitizes LCLs to palmitate-induced apoptosis. Further free fatty acid profiling and metabolic analysis of dual SCD1/FADS2-inhibited LCLs revealed an increase in free unsaturated fatty acids, a reduction of oxidative phosphorylation, and a reduction of glycolysis, thereby linking the activity of SCD1 and FADS2 to overall growth-promoting metabolism. Lastly, we show that SCD1 and FADS2 are important in the growth of clinically derived EBV+ immunoblastic lymphoma cells. Collectively, these data demonstrate a previously uncharacterized role of lipid desaturation in EBV+ transformed B cell proliferation, revealing a metabolic pathway that can be targeted in future anti-lymphoma therapies.

DOI: https://doi.org/10.1371/journal.ppat.1012685