bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2025–11–23
ten papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology
  1. Porcine deltacoronavirus infection promotes intracellular lipid droplet accumulation.
  2. Remodelled cholesteryl ester enriched lipid droplets fuel flavivirus morphogenesis.
  3. Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.
  4. Host immunometabolic regulation through viral sensing pathways.
  5. Disrupted glycosylphosphatidylinositol anchoring induces ER stress and restricts enterovirus infection.
  6. Altered lipid and neurotransmitter metabolism as potential mechanisms of weight gain in women with HIV initiating INSTIs in a pilot study.
  7. Proteomic and metabolomic profiling of plasma reveals physiologic changes in patients with convalescent COVID-19.
  8. Symbiotic Enterococcus faecalis potentiates viral pathogenesis via fructose-1,6-bisphosphate-mediated insect gut epithelial damage.
  9. Coronaviral nsp6 hijacks ERAD machinery to facilitate lipolysis and supply membrane components for DMV growth.
  10. Pseudorabies virus infection induces lymphocyte depletion associated with cellular apoptosis and endoplasmic reticulum stress in the mouse spleen.
  1. Virol J. 2025 Nov 17. 22(1): 378
    Porcine deltacoronavirus infection promotes intracellular lipid droplet accumulation.
    Xiaohui Yang, Haiwen Zhong, Chuanzhao Yu, Jie Cheng, Huijie Jiang, Cuizhen Wang, Changxu Song, Huaqiang Yang.
       BACKGROUND: Viruses critically depend on host lipid metabolism to drive replication, assembly and immune evasion during infection and pathogenesis. While previous studies have demonstrated that certain viruses induce lipid droplet accumulation in infected host cells, lipid droplets have been reported to exert either proviral or antiviral effects across different research contexts. The present study investigates how porcine deltacoronavirus (PDCoV) regulates lipid droplet biogenesis and fatty acid synthesis in LLC-PK1 cells, with the aim of elucidating the potential molecular mechanisms and regulatory gene targets that govern lipid droplet homeostasis during infection.
    METHODS: First, we characterized PDCoV's impact on lipid droplet homeostasis in LLC-PK1 cells using immunofluorescence staining, lipidomic profiling and gene expression analysis. Subsequently, we investigated the molecular mechanisms governing lipid droplets' antiviral effects against PDCoV, focusing on interferon (IFN) response pathway and endoplasmic reticulum (ER) stress signaling. Finally, we employed gene knockout (KO) strategy to study the regulatory gene of lipid metabolism that modulate the efficiency of PDCoV infection.
    RESULTS: PDCoV infection caused significant accumulation of lipid droplets in LLC-PK1 cells. Transcriptional and lipidomic analyses revealed a disruption in lipid metabolism, characterized by altered gene expression and elevated cellular triacylglycerol (TAG) levels. Lipid droplets exhibited co-localization with actively replicating virus, suggesting a potential proviral role of lipid droplets in PDCoV infection. However, excessive lipid droplets accumulation strongly suppressed PDCoV infection. This antiviral effect was linked to enhanced type I/III IFN responses and ER stress. We further identified the pan-coronavirus host factor TMEM41B as a key regulator of lipid droplet homeostasis. TMEM41B KO induced aberrantly enlarged lipid droplets and potently inhibited PDCoV infection. Re-expression of TMEM41B restored both lipid droplet morphology and PDCoV infection, underscoring its role in modulating infection through lipid metabolic regulation.
    CONCLUSIONS: This work delineates host factors and mechanisms governing the lipid droplet-PDCoV interplay, revealing an antiviral strategy via chemical or genetic modulation of lipid droplet homeostasis.
    Keywords:  ER stress; IFN response; Lipid droplet; PDCoV; TMEM41B
    DOI:  https://doi.org/10.1186/s12985-025-03002-3
  2. bioRxiv. 2025 Sep 30. pii: 2025.06.07.658178. [Epub ahead of print]
    Remodelled cholesteryl ester enriched lipid droplets fuel flavivirus morphogenesis.
    Adrianna Banducci-Karp, Sophie Brixton, Pranav N M Shah, Ming-Yuan Li, Georgina Fisher, Joey Riepsaame, Raman Dhaliwal, Katie L Holden, Edward Drydale, James Bancroft, Charlotte E Melia, Gathsaurie Neelika Malavige, Sumana Sanyal.
      Flaviviruses such as dengue and Zika viruses extensively remodel host cell membranes to create specialised replication organelles, but the role of lipid metabolism to generate them remain poorly understood. Through systematic screens of fatty acyl transferase enzymes (MBOAT and zDHHC families) and complementary approaches including CRISPR/Cas9 gene deletions, pharmacological inhibition, proteomics, and photo-crosslinkable cholesterol analogues, we identified cholesteryl ester-enriched lipid droplets (CE-LDs) as critical host components required for flavivirus infection. CE-LD formation is mediated by Sterol O-acyltransferases 1 and 2 (SOAT1/SOAT2), whose activities were upregulated early during infection, coinciding with increased CE-LD formation and transition to liquid crystalline phases. Genetic deletion or pharmacological inhibition of either enzyme resulted in a dramatic ∼100-fold reduction in viral production. Mechanistically, CE-LDs display distinct proteomic signatures, enriched in fatty acid remodelling enzymes, GTPases, and lipid transport proteins. Photo-crosslinking experiments demonstrated direct interactions between LD-derived cholesterol and viral prM, capsid and NS1. Disrupting CE-LD formation via SOAT1/2-deficiency resulted in defective, viral RNA-free replication organelles and complete absence of immature virions. Supporting the physiological and clinical relevance of viral LD exploitation, analysis in iPSC-derived macrophages mirrored findings in Huh7 cells, and dengue patients from a Sri Lankan cohort revealed that central obesity significantly increased the risk of severe dengue haemorrhagic fever. This study establishes CE-LDs as essential host metabolic hubs that enable flavivirus morphogenesis and identifies host LD metabolism as a promising therapeutic target for combating flavivirus infections.
    DOI:  https://doi.org/10.1101/2025.06.07.658178
  3. PLoS Pathog. 2025 Nov 21. 21(11): e1013676
    Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.
    Zhifei Li, Xianfeng Hui, Miaomiao Zheng, Zhicheng He, Wenjing Huai, Binbin Ding, Meilin Jin, Yali Qin, Mingzhou Chen.
      Infection by positive-strand RNA viruses necessitates membrane expansion and elevated phospholipid biosynthesis, whereby fatty acids stored as triacylglycerols in lipid droplets (LDs) are mobilized to promote metabolic processes and membrane biogenesis. The replication organelles (ROs) of coronavirus associate with modified host endomembrane; however, the molecular mechanisms underlying the expansion and modification of these membranes remain poorly understood. Here, we show that viral protein orf3a collaborates with nsp3, nsp4, nsp6 to facilitate the formation of ROs in SARS-CoV-2. Importantly, orf3a targets LDs to ROs, establishing novel membrane contact sites and induces host cell microlipophagy, which supplies essential lipids for RO biogenesis. Subsequently, Following the formation of ROs, nsp3, with assistance from nsp12, indirectly recruits phosphatidylinositol 4-kinase beta (PI4KB) to ROs, to produce phosphatidylinositol 4-phosphate (PI4P). This action creates a PI4P-enriched microenvironment that enhances SARS-CoV-2 replication. Our findings elucidate the mechanism governing RO generation during SARS-CoV-2 infection and suggest that targeting microlipophagy pharmacologically may represent a promising strategy for the development of anti-coronaviruses therapies.
    DOI:  https://doi.org/10.1371/journal.ppat.1013676
  4. Curr Opin Microbiol. 2025 Nov 18. pii: S1369-5274(25)00105-5. [Epub ahead of print]88 102683
    Host immunometabolic regulation through viral sensing pathways.
    Ana Julia Estumano Martins, Thaís Pirola Dos Santos, Wilias Greison Silva Santos, Enzo Triozzi, Pedro M Moraes-Vieira.
      Viruses are intracellular pathogens that have profoundly influenced biological evolution and continue to threaten global health through outbreaks such as influenza and COVID-19. Their ability to evade host immunity stems from evolutionary adaptations that manipulate cellular defense mechanisms. A critical aspect of virus-host interactions involves cellular receptors, which facilitate viral entry and trigger immune signaling. Among these, pattern recognition receptors (PRRs) and other proteins serve as key sensors of viral components, coordinating immune responses while reprogramming host metabolism to sustain antiviral defenses. However, many viruses hijack these metabolic changes to enhance replication, evade immune surveillance, or dysregulate cytokine production. This review explores how host cell virus-sensitive proteins, particularly PRRs and metabolically active proteins, modulate cellular metabolism during infection, shaping immune outcomes and revealing potential therapeutic targets for antiviral intervention.
    DOI:  https://doi.org/10.1016/j.mib.2025.102683
  5. PLoS Pathog. 2025 Nov;21(11): e1013685
    Disrupted glycosylphosphatidylinositol anchoring induces ER stress and restricts enterovirus infection.
    Shangrui Guo, Xinyu Li, Meng Xun, Yingli He, Andrew W Tai, Hongliang Wang.
      Many positive-sense RNA viruses, including viruses from the Picornaviridae, Coronaviridae and Flaviviridae family, exploit endoplasmic reticulum (ER)-derived membrane structures as sites of genome replication. Here we use a pooled CRISPR genetic screening strategy to identify glycosylphosphatidylinositol (GPI) anchor biosynthesis and transfer genes as host factors for echovirus 7 infection. In addition to supporting the biogenesis of CD55, which is a GPI anchor protein and an entry factor for some echoviruses, the GPI anchor synthesis machinery also supports several other enterovirus infections by enhancing viral replication and replication organelle biogenesis. Disruption of GPI anchor transfer machinery compromises ER integrity and causes ER stress. Consistent with these findings, ER-resident sensor, inositol-requiring protein 1α (IRE1α) is activated and regulated IRE1-dependent decay of mRNA (RIDD) is detected to reduce ER stress. Interestingly, enterovirus viral RNA, but not Hepatitis C Virus RNA, is degraded during this process due to specific sequences in the Untranslated Region (UTR). This study revealed novel links between GPI anchoring, ER stress and enterovirus infection, and illuminates new host targets for antiviral therapy.
    DOI:  https://doi.org/10.1371/journal.ppat.1013685
  6. J Acquir Immune Defic Syndr. 2025 Nov 18.
    Altered lipid and neurotransmitter metabolism as potential mechanisms of weight gain in women with HIV initiating INSTIs in a pilot study.
    Jessica A Alvarez, Sami Teeny, Chin-An Yang, C Christina Mehta, Qian Yang, Dean P Jones, Young-Mi Go, Anandi Sheth, Ighovwerha Ofotokun, Mohammed K Ali, Thomas R Ziegler, Cecile D Lahiri.
       OBJECTIVE: This pilot study used metabolomics to provide insight into metabolic alterations of INSTI-associated weight gain among women with HIV (WWH).
    METHODS: The study included 33 virally suppressed WWH who switched to or added an INSTI. Plasma samples collected 6-12 months pre- (Visit 1) and 1-6 months post INSTI add/switch (Visit 2) were analyzed with liquid chromatography-mass spectrometry-based high-resolution metabolomics. The baseline plasma metabolome and changes in metabolomic signatures (from Visit 1 to Visit 2) were compared in women who experienced ≥ 5% weight gain (n=18) over 1-2 years vs those who maintained/lost body weight (n=15).
    RESULTS: Median age was 53 (Q1 47, Q3 55) yrs, 94% were Black, baseline BMI was 34.2 (Q1 30.6, Q3 38.5) kg/m2. Median weight change was +9.20 kg (Q1-Q3 6.77-15.13 kg) and -0.68 kg (Q1-Q3 -5.14 to 0.00 kg) for the weight gain vs maintained/lost weight groups, respectively. A total of 820 metabolites spanning 9 enriched metabolic pathways, including amino acid (e.g., tryptophan) and micronutrient pathways (e.g., vitamin E) differed between weight groups before INSTI use (p<0.05). A total of 1147 metabolites spanning 10 enriched pathways, particularly lipid pathways, exhibited a significant group x time interaction effect (p<0.05), with an overall pattern of decreased free fatty acids over time among women who gained weight.
    CONCLUSIONS: Several metabolic pathways at baseline and within 6 months were associated with weight gain in women initiating INSTIs. Acute changes in lipid metabolism following INSTI initiation provide potential insight into the pathophysiology of weight gain in this population.
    Keywords:  HIV; integrase strand transfer inhibitor; metabolism; metabolomics; obesity; overweight
    DOI:  https://doi.org/10.1097/QAI.0000000000003799
  7. Metabolomics. 2025 Nov 15. 21(6): 168
    Proteomic and metabolomic profiling of plasma reveals physiologic changes in patients with convalescent COVID-19.
    Lei Wang, Ying Zhang, Lixin Bao, Yubin Guo, Qingshan Hai, Jing Wu, Tinglin Wang, Guotong Sun, Xiuwen Liang.
       BACKGROUND: This study aimed to analyze the molecular composition and physiological changes in the plasma of patients with convalescent coronavirus disease 2019 (COVID-19).
    METHODS: Plasma samples from 29 hospitalized patients recovering from COVID-19 and 30 uninfected controls were analyzed using untargeted metabolomics and data-independent acquisition mass spectroscopy proteomic analyses. Integrative metabolomic-proteomic analysis was then conducted to construct a protein-metabolite interaction network.
    RESULTS: Untargeted metabolomic profiles revealed 415 differential metabolites, with 28.05% of the metabolites belonging to lipids and lipid-like molecules, most of which were upregulated in patients with convalescent COVID-19, such as sphingolipids. Differential metabolites were involved in taste transduction, thermogenesis, and sphingolipid metabolism. Proteomic analysis identified 947 differentially expressed proteins, which were mainly involved in immunoinflammation-related pathways, such as complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation. Several significant pathways were influenced by differential metabolites and proteins, such as estrogen signaling, ferroptosis, and neurodegeneration-associated pathways.
    CONCLUSION: This study revealed differential metabolite and protein compositions in the plasma of patients with convalescent COVID-19 compared with uninfected controls. The main physiological changes were associated with the pathology of this disease, suggesting that the phenotype of patients with convalescent COVID-19 did not return to a phenotype similar to that of uninfected controls.
    Keywords:  COVID-19; Convalescent plasma; Metabolomics; Multiomics; Proteomics
    DOI:  https://doi.org/10.1007/s11306-025-02337-w
  8. NPJ Biofilms Microbiomes. 2025 Nov 20. 11(1): 215
    Symbiotic Enterococcus faecalis potentiates viral pathogenesis via fructose-1,6-bisphosphate-mediated insect gut epithelial damage.
    Yanchun Deng, Hongxia Zhao, Li Zhang, Sa Yang, Dexin Zou, Mingxiao Ma, Chunsheng Hou.
      Chinese sacbrood virus (CSBV) is highly lethal to Asian honey bee (Apis cerana) larvae. While gut symbionts are known to regulate viral infection, their role in CSBV pathogenesis remains poorly understood. Through 16S rRNA gene sequence analysis of the field-collected honey bees, we found that the larvae had a substantially higher relative abundance of Enterococcus than pupae or adults. Metagenome sequencing analysis of field-collected larvae demonstrated that CSBV infection significantly induced more than 45-fold enhancement in the abundance of Enterococcus faecalis, an opportunistic pathogen implicated in the development of purulent cystic lesions. In microbiota-free (MF) bees, colonization with E. faecalis markedly suppressed phospholipid metabolism and elevated levels of 4-guanidinobutyric acid and fructose-1,6-bisphosphate (FBP). These metabolic changes were associated with cytotoxicity and apoptosis, which worsened goblet cell damage and thereby facilitated CSBV infection, as indicated by metabolomics and pathological section analysis. Crucially, exogenous FBP administration directly enhanced cytotoxicity and apoptosis of gut in CSBV-infected MF bees, mirroring the CSBV susceptibility was mediated by E. faecalis. Our study unveiled a symbiotic bacteria's involvement in promoting RNA virus infection through metabolic reprogramming and epithelial barrier dysfunction, providing new insights into host-microbe-virus interactions in pollinators.
    DOI:  https://doi.org/10.1038/s41522-025-00843-2
  9. Nat Commun. 2025 Nov 18. 16(1): 10094
    Coronaviral nsp6 hijacks ERAD machinery to facilitate lipolysis and supply membrane components for DMV growth.
    Shu-Rui Liu, Yuzheng Zhou, Jinwei Li, Zhaohuan Wang, Yu Ye, Jiafan Miao, Keda Shi, Birong Zheng, Binbin Ding, Jian Pan, Chun-Mei Li, Yiping Li, Panpan Hou, Deyin Guo.
      The positive-strand RNA ( + RNA) viruses extensively remodel cellular endomembranes to facilitate viral replication, with coronaviruses forming a specialized viral replication organelle (RO) known as double-membrane vesicles (DMVs). These DMVs serve as platforms for viral replication and shield viral RNA from host immune recognition. However, the biogenesis, structural organization, and physiological properties of DMVs remain poorly understood. In this study, we demonstrate that the coronavirus non-structural protein 6 (nsp6) anchors DMVs to lipid droplets (LDs), hijacks the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery to degrade PLIN2, and redirects fatty acids (FAs) from LDs to DMVs, thereby supplying lipids for DMV growth. Furthermore, nsp6 anchors ERAD-derived vesicles to DMVs, directly refurnishing membrane components for DMV expansion. Disruption of lipolysis or ERAD impairs DMV formation and inhibits coronaviral replication. We further validated the antiviral effects of ERAD inhibition in female mice in vivo. Our findings elucidate the mechanisms and functional significance of virus-induced organelle remodeling and DMV biogenesis. Given the conservation of viral ROs across +RNA viruses, these structures represent a promising and attractive target for the development of broad-spectrum antiviral therapies.
    DOI:  https://doi.org/10.1038/s41467-025-65118-y
  10. BMC Vet Res. 2025 Nov 17. 21(1): 673
    Pseudorabies virus infection induces lymphocyte depletion associated with cellular apoptosis and endoplasmic reticulum stress in the mouse spleen.
    Kun Liu, Hangkuo Xin, Kuiyang Meng, Long Zhao, Shengyu Lin, Wei Chen, Qingqing Xie, Ting Zhu.
       BACKGROUND: The spleen is a highly organized lymphoid organ with a critical role in antimicrobial immune responses. Pseudorabies virus (PRV) is widely recognized for its ability to induce immunosuppression, with the spleen being one of the primary parenchymal organs of target. Viral infections often disrupt endoplasmic reticulum (ER) homeostasis, leading to ER stress and subsequent apoptosis. This study aimed to investigate the relationship between PRV-induced spleen damage and ER stress.
    RESULTS: Both classical (Min-A) and variant (SX-2018) PRV strains caused significant histopathological damage in the mouse spleen, including marked reductions in CD8+ T cell populations and increased lymphocyte apoptosis. Further analyses revealed that PRV infection triggered ER stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway in the spleen. Notably, treatment with the ER stress inhibitor 4-phenylbutyric acid(4-PBA) mitigated lymphocyte depletion and improved survival rates in PRV-infected mice.
    CONCLUSIONS: PRV infection leads to lymphocyte depletion in mouse spleens, closely associated with ER stress and apoptosis.
    Keywords:  4-PBA; Apoptosis; CD8+ t cell; ER stress; PRV; Spleen
    DOI:  https://doi.org/10.1186/s12917-025-05125-9
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