bims-mevinf 2025-12-07 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–12–07
fourteen papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

Decoding the metabolic crosstalk between glycolysis and RNA viral pathogenesis.
Isochlorogenic acid A impairs hepatitis B virus replication by interference with various steps of hepatitis B virus life cycle involving HO-1-mediated ROS modulation.
The roles of sugar metabolism mechanisms and metabolites in viral infections.
The gut-liver-virus axis in hepatitis B and C: microbiota, immunometabolism, and exosome-mediated therapeutic opportunities.
Lipid profiling of rabies virus infection in mice and cell lines.
Resveratrol can inhibit porcine reproductive and respiratory syndrome virus infection in vitro and in vivo by inhibiting PI3K/Akt signaling pathway.
Integrated systems vaccinology reveals distinct metabolic responses to SARS-CoV-2 infection and DNA-based vaccines in ferrets.
Quantitative proteomic analysis identifies the unfolded protein response as a host pathway co-opted by ASFV to promote replication.
A CRISPR-based Genome-wide Loss-of-function Screen Defines a Role of Host Metabolism in Regulating Hepatitis B Virus Infection.
Ribonucleotide reductase subunit M2 mediates the mTOR pathway to recruit furin endoprotease and promote maturation of dengue virus.
Genome-scale CRISPR screen identifies host factors associated with bovine parainfluenza virus 3 infection.
Fucose dependent rotavirus and norovirus require fucosidase activity for optimal replication.
The influence of chronic hepatitis B virus infection on fatty acid composition in erythrocyte membranes and plasma, and its effect on lipoxin A4 and resolvin D1 levels.
HCMV immediate-early protein IE2 induces neurotoxicity and hearing loss by disrupting TSC2-mTOR signaling and metabolic homeostasis.

Virology. 2025 Nov 29. pii: S0042-6822(25)00380-0. [Epub ahead of print]615 110766

Decoding the metabolic crosstalk between glycolysis and RNA viral pathogenesis.

Vijay Singh Bohara, Sachin Kumar.

  RNA viruses induce metabolic reprogramming in the host cells by shifting metabolism towards enhanced glycolysis, rapidly converting glucose to lactate, a phenomenon known as the Warburg effect. This metabolic shift supports viral replication by providing essential macromolecular precursors and energy. They regulate key components of glycolysis, including glucose transporters and glycolytic enzymes, to facilitate increased glucose uptake and its flux. Glycolysis is also crucial for the activation of immune cells and the regulation of cytokine production. This review summarises the molecular mechanisms driving these metabolic alterations to better understand the virus-host interactions. The factors regulating these mechanisms can be potential therapeutic targets for controlling viral infections.

Keywords:  Cytokines; Glucose transporters; Hypoxia-inducible factor; Interferons; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.virol.2025.110766
Antiviral Res. 2025 Dec 04. pii: S0166-3542(25)00249-9. [Epub ahead of print]245 106323

Isochlorogenic acid A impairs hepatitis B virus replication by interference with various steps of hepatitis B virus life cycle involving HO-1-mediated ROS modulation.

Giscard Wilfried Koyaweda, Mirco Glitscher, Anja Schollmeier, Daniela Bender, Eberhard Hildt.

  Chronic hepatitis B virus (HBV) infection is a major health problem, affecting around 254 million people worldwide. Current treatments have side effects and can lead to resistance. Therefore, natural compounds derived from plants are being studied as potential antivirals. Isochlorogenic acid A (ICAA), which is derived from caffeoylquinic acid, exerts antiviral and hepatoprotective effects. The antioxidant effect of ICAA, triggered by upregulation of heme oxygenase 1 (HO-1), has been suggested as potential antiviral mechanism. However, the underlying mechanisms remain enigmatic. Our aim is to elucidate the mode of action of the antiviral effect of ICAA on HBV. Stable or transient transfected cells expressing HBV as well as HBV-infected cells were instrumental. (Sub)viral particles were characterized by biophysical and biochemical methods. Subcellular distribution of viral proteins was studied using confocal laser scanning microscopy. Viral genomes and transcripts were quantified by qPCR. Treatment with ICAA decreased levels of HBV surface and e antigens (HBsAg and HBeAg), as well as viral transcripts, genomes and most important cccDNA. Furthermore, impaired virus assembly was evident from accumulation of naked capsids suggesting improper capsid formation and impaired envelopment. ICAA-dependent effects on HBV correlate with upregulation of HO-1 and modulation of intracellular ROS Our data indicate a possible link between changes in the intracellular ROS level and altered free -SH groups in viral structural proteins, possibly influencing proper disulphide bond formation and thereby assembly. In conclusion ICAA-dependent effects on HBV life cycle are based on several pillars as modulation of intracellular ROS and impaired morphogenesis and replication.

Keywords:  HBV envelopment; HBV morphogenesis; HBV naked capsid; Heme oxygenase 1 (HO-1); Isochlorogenic acid a; Reactive oxygen species (ROS); cccDNA

DOI:  https://doi.org/10.1016/j.antiviral.2025.106323
Virology. 2025 Nov 28. pii: S0042-6822(25)00378-2. [Epub ahead of print]615 110764

The roles of sugar metabolism mechanisms and metabolites in viral infections.

Jieyi He, Xianghong Ju, A M Abd El-Aty, Xiaoxi Liu, Xiaowen Li.

  Viral infections pose a persistent challenge to global health by triggering sophisticated molecular interactions and extensive metabolic reprogramming within host organisms. Glycolysis-a central energy metabolism pathway-is dynamically and bidirectionally regulated during infection, reflecting a continuous metabolic interplay between pathogen and host. Rather than maintaining a static metabolic state, glycolytic flux is shaped by competing demands: viruses actively stimulate glycolysis to support replication, while hosts suppress it as a defensive strategy. This regulatory balance shifts across distinct stages of infection-from viral entry and replication peaks to immune clearance-resulting in phase-specific fluctuations in glycolytic activity that reveal a dynamic metabolic tug-of-war. In this review, we synthesize current understanding of how viruses recurrently activate host glycolysis to enhance replication, detailing conserved mechanisms of metabolic hijacking and the multilayered counterstrategies employed by the host. We further evaluate emerging therapeutic approaches, including targeted glycolytic inhibitors and combined immunomodulatory regimens, while addressing challenges related to specificity and efficacy. Finally, we highlight promising research directions such as tissue-specific nanodelivery platforms and single-cell multi-omics integration, which together offer a conceptual framework for developing next-generation antiviral therapies.

Keywords:  Antiviral therapy; Glycolysis; Metabolic reprogramming; Viral infection

DOI:  https://doi.org/10.1016/j.virol.2025.110764
Naunyn Schmiedebergs Arch Pharmacol. 2025 Nov 29.

The gut-liver-virus axis in hepatitis B and C: microbiota, immunometabolism, and exosome-mediated therapeutic opportunities.

Kainat Raziq, Syed Qaswar Ali Shah, Mirza Naveed Shahzad, Umm E Ummara, Mishal Subhan, Muhammad Muzammil Nazir.

  Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain a major global health burden, leading to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Despite advancements in vaccination and antiviral therapies, viral persistence, immune evasion, and disease progression continue to challenge global elimination goals. Recent evidence suggests that the gut-liver-virus axis, involving microbiota dysbiosis, immunometabolic reprogramming, and exosome mediated signaling, plays a central role in HBV and HCV related pathogenesis. A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar from January 2000 to August 2025. Studies were screened according to the PICO framework, focusing on HBV/HCV persistence, gut microbiota dysbiosis, immunometabolic changes, exosome-mediated communication, and therapeutic interventions. A total of 100 eligible studies, including clinical, preclinical, and mechanistic investigations, were synthesized. The analysis revealed that HBV and HCV infections remodel the gut liver axis through depletion of short-chain fatty acid (SCFA) producing taxa, enrichment of pro-inflammatory bacteria, and dysregulated bile acid and lipopolysaccharide metabolism. Viral persistence is sustained by immunometabolic rewiring, including glycolysis upregulation, lipid accumulation, and tryptophan kynurenine pathway activation, leading to T-cell exhaustion and immune suppression. Exosomes derived from infected hepatocytes and tumors facilitate viral spread, immune evasion, and oncogenesis while emerging as potential biomarkers and therapeutic nanocarriers. Collectively, these interconnected mechanisms drive inflammation, fibrosis, cirrhosis, and progression to HCC. The progression of HBV/HCV infections is governed by a complex interplay of viral persistence, gut microbiota alterations, metabolic reprogramming, and exosome-mediated communication. Targeting these pathways through microbiota-directed therapies, metabolic modulators, and exosome-based interventions offers promising opportunities for precision medicine. Future studies employing multi-omics integration, validated models, and longitudinal cohorts are required to establish causality and translate mechanistic insights into effective clinical strategies for preventing HBV/HCV associated cirrhosis and cancer.

Keywords:  Biomarkers; Cirrhosis; Exosomes; Gut–liver axis; Hepatitis B virus; Hepatitis C virus; Hepatocellular carcinoma; Immunometabolism; Microbiota dysbiosis; Precision medicine

DOI:  https://doi.org/10.1007/s00210-025-04856-8
Virology. 2025 Dec 03. pii: S0042-6822(25)00384-8. [Epub ahead of print]615 110770

Lipid profiling of rabies virus infection in mice and cell lines.

Zhanzhong Zhao, Gangbin Tang, Xinghui Zhao, Gang Li.

  The lipid profile of rabies virus infection in hosts remains unknown. Based on the histopathology and neuroinvasiveness, one Flury-LEP of three rabies virus strains was selected and utilized in vitro and in vivo studies. Samples (tissue, plasma and cell pellet) were collected from a mouse model and cell model infected with Flury-LEP strain, and analyzed using a semi-quantitative, untargeted method based on liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS-MS). The resulting lipidomics data were then subjected to statistical analysis. The lipid profile for specific tissues (brain, heart, liver, spleen, lungs, kidneys, intestines, spinal cord, testes and ovaries), plasma (male and female) and cell lines (BHK21 and N2a) were obtained. In mice, the histopathological changes in the tissues, might be associated with changes of the local and circulating lipid profile. Overall, lipid profiling of mice and cells infected with Flury-LEP strain has been achieved, contributing to the understanding of host lipid metabolism and rabies virus-host interactions.

Keywords:  Cell line; Flury-LEP; Mice; Phospholipid; Rabies virus; Sphingolipid

DOI:  https://doi.org/10.1016/j.virol.2025.110770
Vet Microbiol. 2025 Nov 29. pii: S0378-1135(25)00459-6. [Epub ahead of print]312 110823

Resveratrol can inhibit porcine reproductive and respiratory syndrome virus infection in vitro and in vivo by inhibiting PI3K/Akt signaling pathway.

Yaping Chen, Wenshuang Chen, Xinqi Song, Xinyi Zhao, Li Yang, Ruoyu Zhao, Meilong Song, Bingbing Zhang, Dongbo Sun.

  Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically costly pathogens in global pig industry, causes reproductive dysfunction in pregnant sows and respiratory distress in piglets. Resveratrol (RES), a polyphenolic compound, exhibits antiviral properties. Despite its recognized bioactivity, the potential antiviral efficacy against PRRSV remains underexplored. This research investigated the effect of RES in PRRSV infection and its underlying molecular mechanism. The animal attack tests showed that RES markedly improved clinical symptoms and reduced lung tissue damage in piglets infected with PRRSV. In vitro experiments further revealed RES suppress PRRSV replication within Marc-145 cells. Mechanistic investigations revealed that the PI3K/Akt signaling pathway was the crucial passage. RES directly acted on PRRSV particles by down-regulating Nsp3, thereby effectively inhibiting viral replication in cells. Specifically, we identified the PYDP motif of Nsp3 as crucial for binding to the key protein p85 in the PI3K/Akt signaling pathway, highlighting a pivotal amino acid site for viral modulation of this pathway. Furthermore, in host cells, RES inhibited PRRSV replication by suppressing the PI3K/Akt pathway, involving coordinated regulation of autophagy and ferroptosis. Notably, RES directly suppressed viral replication by inhibiting autophagy and ferroptosis, with evident cross-talk between these processes. Collectively, our findings unveil a novel mechanism of the cross-talk between autophagy and ferroptosis in regulating PRRSV infection. RES exhibited inhibitory effects on PRRSV both in vivo and in vitro by targeting the PI3K/Akt pathway. These findings will provide important insights for developing prevention and treatment strategies against PRRS.

Keywords:  Autophagy; Cross-talk; Ferroptosis; PRRSV; Resveratrol

DOI:  https://doi.org/10.1016/j.vetmic.2025.110823
Biomed Pharmacother. 2025 Dec 04. pii: S0753-3322(25)01052-2. [Epub ahead of print]193 118858

Integrated systems vaccinology reveals distinct metabolic responses to SARS-CoV-2 infection and DNA-based vaccines in ferrets.

Gustaf Ahlén, Anoop Ambikan, Flora Mikaeloff, Sefanit Rezene, Jingyi Yan, Negin Nikouyan, Chandrashekar Bangalore Revanna, Sofia Appelberg, Ali Mirazimi, Matti Sällberg, Ujjwal Neogi, Soham Gupta.

  Understanding how infection and vaccination reshape systemic metabolism is key to defining protective immunity against SARS-CoV-2. Using a ferret model, we performed untargeted serum metabolomics in two experimental settings: SARS-CoV-2 infection alone, and vaccination followed by viral challenge. Ferrets were immunized with four vaccines: a multigenic DNA-construct encoding receptor-binding domain, membrane, and nucleoprotein (OC2); a nucleoprotein-only DNA vaccine (OC12); a recombinant spike protein with QS-21 adjuvant (S+QS21); or a control hepatitis-B/D DNA vaccine (Hep-B/D). SARS-CoV-2 infection induced distinct systemic changes, including reduced lipid remodeling and enrichment of amino acid, carbohydrate, and energy pathways (notably glutathione and methionine-cysteine metabolism and the tricarboxylic acid cycle). Vaccination induced broader, immunogen-specific metabolic remodeling. Post-vaccination, S+QS21 triggered extensive early alterations, mainly suppressing lipid and amino acid pathways. In contrast, OC2 produced balanced remodeling across amino acid, lipid, nucleotide, and glutathione-related metabolism, with temporally consistent shifts. Following viral challenge, OC2 maintained sustained remodeling with enrichment of redox-associated metabolites, including γ-glutamyl amino acids and acylcarnitines, coinciding with anti-spike and anti-nucleoprotein IgG responses and complete viral clearance. OC12 elicited strong anti-nucleoprotein antibodies but limited remodeling and incomplete protection, while S+QS21 showed moderate post-challenge responses with partial clearance. Hep-B/D induced minimal changes and no protection. These findings show vaccination induces immunogen-specific metabolic programs, with OC2 eliciting the broadest remodeling linked to protective immunity. To our knowledge, this is the first demonstration that DNA-based multigenic SARS-CoV-2 vaccination induces systemic metabolic reprogramming in ferrets, linking remodeling to antibody responses and viral clearance. Metabolomics informs host-vaccine interactions within a systems vaccinology framework.

Keywords:  DNA Vaccines; Ferret Model; Immunometabolism; Metabolomics; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.biopha.2025.118858
mBio. 2025 Dec 05. e0324225

Quantitative proteomic analysis identifies the unfolded protein response as a host pathway co-opted by ASFV to promote replication.

Danyang Zhang, Baohong Liu, Huanan Liu, Ruoqing Mao, Weijun Cao, Xiangle Zhang, Fayu Yang, Yichao Wang, Chaochao Shen, Shilei Zhang, Zixiang Zhu, Haixue Zheng.

  African swine fever (ASF), caused by the African swine fever virus (ASFV), is a highly contagious disease that affects pigs, resulting in substantial economic losses in the global pig industry. A comprehensive understanding of viral-host protein interactions can facilitate the discovery of therapies for viral infection. In this study, we employ a 4D label-free quantitative proteomics approach to profile a comprehensive protein dynamics analysis in ASFV-infected pigs, identifying over 6,000 proteins across multiple organs. Our results reveal coordinated interorgan responses characterized by inflammatory activation and interferon signaling in defense against ASFV. The protein-protein interaction network analysis uncovers ASFV-induced functional modules, including the unfolded protein response (UPR), innate immune signaling, and inflammation, which are conserved across tissues. Notably, ASFV robustly activates all three branches of the UPR both in vivo and in vitro to promote viral replication. Furthermore, we identify that the virus-encoded protein D117L interacts with multiple UPR-related host proteins, thereby directly triggering UPR activation. Collectively, this study delineates the organ-specific proteomic landscape of ASFV infection, providing valuable insights into virus-host interactions and offering potential therapeutic targets for ASF.IMPORTANCEAfrican swine fever virus (ASFV) has caused severe consequences for the global pig industry. In this study, we conducted a multi-organ proteomic analysis using a 4D label-free quantitative proteomics approach and mapped the organ-specific proteomic landscape during ASFV infection. This work overcomes the limitations of most existing studies, which are primarily restricted to in vitro cell models and provide a more comprehensive understanding of ASFV infection and pathogenesis. Notably, the viral D117L protein is identified as a critical modulator of host cellular responses, directly subverting the unfolded protein response (UPR) pathway through specific interactions with host UPR-associated proteins. Collectively, our work lays the foundation for understanding the pathogenesis of ASFV, providing potential therapeutic strategies against African swine fever.

Keywords:  African swine fever virus; proteomics; replication; unfolded protein response

DOI:  https://doi.org/10.1128/mbio.03242-25
Mol Ther. 2025 Dec 01. pii: S1525-0016(25)01019-6. [Epub ahead of print]

A CRISPR-based Genome-wide Loss-of-function Screen Defines a Role of Host Metabolism in Regulating Hepatitis B Virus Infection.

Tadashi Inuzuka, Karim Mouzannar, Min Zhang, Regina Umarova, Seung Bum Park, Takuro Uchida, Christopher D Ma, T Jake Liang.

Hepatitis B virus (HBV) co-opts and interacts with an extensive array of host factors for productive infection. Herein, we developed an HBV reporter virus expressing red fluorescent protein (HBV-RFP) that is suitable for a CRISPR-based genome-wide screen for HBV host-dependency factors. HepG2NTCP/Cas9 cells were transduced with a pooled lentiviral library of single-guide RNA (sgRNA) targeting 19,114 human genes, edited and infected with HBV-RFP. RFP-low cells were sorted using fluorescence-activated cell sorting. The sorted cells were expanded and underwent two additional rounds of infection and sorting to enrich for sgRNA-targeted proviral host factors. By next-generation sequencing and bioinformatic analyses, we identified 63 genes as candidate host proviral factors, including known HBV proviral factors: RXRA, POLL, LDLR and NTCP. Among the novel candidate genes, knock-out of 12 genes significantly decreased HBV replication markers. Validation using siRNA knock-down in primary human hepatocytes confirmed several factors including the monoacylglycerol acyltransferase 2 (MOGAT2) gene as a bona fide HBV pro-viral factor. Further analysis with MGAT2 inhibitors demonstrated that inhibition of MOGAT2 activity impairs HBV transcription and replication. Our study demonstrates the value of the HBV reporter system in identifying previously unrecognized host metabolic factors important for HBV infection, offering a potential avenue for therapeutic development.

DOI: https://doi.org/10.1016/j.ymthe.2025.11.032
iScience. 2025 Dec 19. 28(12): 113998

Ribonucleotide reductase subunit M2 mediates the mTOR pathway to recruit furin endoprotease and promote maturation of dengue virus.

Bouchra Kitab, Michinori Kohara, Kyoko Tsukiyama-Kohara.

  Dengue virus (DENV) maturation involves calcium-dependent endoprotease furin, which cleaves the precursor membrane (prM) into the M protein in the trans-Golgi network, facilitating the release of infectious virus. Here, we demonstrate that ribonucleotide reductase subunit M2 (RRM2) recruits furin to mediate the cleavage of the DENV prM protein. Silencing of RRM2 reduced furin expression, leading to the accumulation of uncleaved prM in infected cells, increased intracellular DENV RNA, and diminished infectious virus titers in the supernatant. DENV infection prompted colocalization and interaction between RRM2 and furin in hepatoma cells and liver tissues of infected mice, with enhancement of RRM2 expression and furin stability. Silencing RRM2 impeded the effects of mammalian target of rapamycin (mTOR), leading to decreased furin expression. Additionally, mTOR overexpression reduced uncleaved prM and intracellular viral RNA while increasing furin levels in DENV-infected cells. These findings highlighted a DENV maturation process, which is fine-tuned by the RRM2-mTOR-mediated pathway.

Keywords:  Molecular biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2025.113998
Virulence. 2025 Dec;16(1): 2589554

Genome-scale CRISPR screen identifies host factors associated with bovine parainfluenza virus 3 infection.

Yuanchen Geng, Chuanwen Jiang, Huaiyi Zhang, Hao Yang, Yongchong Peng, Yingyu Chen, Changmin Hu, Hailong Liu, Sheng Li, Huanchun Chen, Shengsong Xie, Aizhen Guo.

  Bovine parainfluenza virus type 3 (BPIV-3) is a major pathogen associated with the bovine respiratory disease complex. However, the limited understanding of host factors crucial for BPIV-3 replication has hindered the development of effective preventive and therapeutic strategies. To tackle this critical issue, we constructed a bovine genome-wide CRISPR/Cas9 knockout library in Madin-Darby bovine kidney cells, which was then used to systematically identify and characterize the host genes essential for BPIV-3a replication. Subsequently, 10 genes were validated using both RT-qPCR and viral titration assays. Furthermore, through gene knockout or knockdown and rescue experiments, we identified three key genes required for BPIV-3a replication: Wnt family member 5A (WNT5A), solute carrier family 16 member 13 (SLC16A13), and selenoprotein N (SELENON). However, their effects on viral adhesion and internalization varied. WNT5A was involved in both processes, SLC16A13 participated solely in internalization, while SELENON had no significant impact on either. Beyond BPIV-3a, these three genes were also found to be essential for the infection of BPIV-3c and Bovine enterovirus. In conclusion, this study offers novel insights into the molecular mechanisms governing the replication and pathogenesis of BPIV-3a, BPIV-3c, and bovine enterovirus within host cells, thereby providing a foundation for identifying potential targets in the development of novel antiviral strategies.

Keywords:  BPIV-3; CRISPR screen; SELENON; SLC16A13; WNT5A; host factors

DOI:  https://doi.org/10.1080/21505594.2025.2589554
Npj Viruses. 2025 Nov 29. 3(1): 80

Fucose dependent rotavirus and norovirus require fucosidase activity for optimal replication.

Nazaret Peña-Gil, Nanci Santos-Ferreira, Sonia Llanos-Villatoro, Ana Melero, Roberto Cárcamo-Calvo, Sergi López-Navarro, Cristina Santiso-Bellón, Javier Buesa, Vicente Monedero, Maria J Yebra, Joana Rocha-Pereira, Roberto Gozalbo-Rovira, Jesús Rodríguez-Díaz.

Rotavirus (RV) and norovirus (NoV) are enteric viruses responsible for acute gastroenteritis that require fucosylated histo-blood group antigens for infection in humans. How the interaction of these viruses with fucosylated glycans modulates infection is not well understood. Treatment of target cells with a bacterial α1,2 fucosidase enzyme reduced RV and NoV infection in vitro, but increased replication in vivo. Conversely, the fucosidase inhibitor 1-deoxyfuconojirimycin impaired viral replication in both models, highlighting the role of fucosidase activity in fucose-dependent enteric virus infection. This underscores the complexity of fucose interactions for these viruses and implicates fucosidase activity as a potential antiviral target for RV and NoV.

DOI: https://doi.org/10.1038/s44298-025-00164-3
Folia Med Cracov. 2025 Jul 31. 65(2): 153-162

The influence of chronic hepatitis B virus infection on fatty acid composition in erythrocyte membranes and plasma, and its effect on lipoxin A4 and resolvin D1 levels.

Joanna Gdula-Argasińska, Jacek Czepiel, Agata Pietrzycka, Artur Jurczyszyn, Paweł Wołkow, Agnieszka Borys, Katarzyna Stażyk, Monika Bociąga-Jasik.

   AIM: This study aimed to assess the impact of chronic hepatitis B on fatty acids (FA) composition in erythrocyte membranes (RBC) and plasma, and its effect on lipoxin A4 and resolvin D1 levels.
MATERIALS AND METHODS: Sixty participants were enrolled: 30 hepatitis B patients (15 with cirrhosis, 15 without) and 30 healthy controls. Fatty acids content in plasma and RBC membranes was analyzed by gas chromatography. Serum lipoxin A4 (LXA4) and resolvin D1 (RvD1) were measured via enzyme immunoassay. Principal component analysis (PCA) assessed correlations between fatty acid composition, LXA4 and RvD1 levels.
RESULTS: Hepatitis B patients with cirrhosis exhibited significantly lower plasma lipoxin A4 (1812 pg/mL) compared to controls (2230 pg/mL) and non-cirrhotic hepatitis B patients (2453 pg/mL). Plasma n-3 FA levels (15.4% vs. 8.7%) and the n-3/n-6 ratio (0.8 vs. 0.4) were significantly reduced in cirrhotic patients. PCA data revealed associations between LXA4 and saturated fatty acids, and between n-3 FA and RvD1 pathways, suggesting disrupted lipid-mediated inflammation resolution. Erythrocyte membranes showed elevated trans C18:1 in cirrhotic hepatitis B.
CONCLUSIONS: Chronic HBV infection, especially with cirrhosis, alters fatty acid profiles and reduces lipoxin A4 level, contributing to persistent hepatic inflammation and highlighting potential lipid-targeted therapies.

Keywords:  fatty acids; hepatitis B; lipoxinA4; plasma; resolvin D1

DOI:  https://doi.org/10.24425/fmc.2025.156132
J Neuroinflammation. 2025 Dec 02.

HCMV immediate-early protein IE2 induces neurotoxicity and hearing loss by disrupting TSC2-mTOR signaling and metabolic homeostasis.

Meng Yu, Zhifei Wang, Yunyang Wang, Xianjuan Zhang, Zhun Wei, Bin Wang.

  Sensorineural hearing loss (SNHL) caused by human cytomegalovirus (HCMV) infection involves alterations in both the central auditory pathways and cochlear structures. Immediate early (IE) proteins are critical for HCMV pathogenicity and have been associated with neurodevelopmental disorders; however, their contribution to HCMV-associated SNHL remains unclear. Here, we generated transgenic mouse models expressing HCMV IE1 and IE2 protein to investigate their effects on auditory function and cochlear pathology. Auditory brainstem response (ABR) measurements revealed that expression of IE2, but not IE1, led to significantly elevated ABR thresholds and impaired auditory processing. IE2-transgenic mice exhibited synaptic loss, hair cell degeneration, and neuronal atrophy in auditory regions. scRNA-seq analysis indicated broad activation of inflammatory pathways and cytokines within the cochlea, along with disruptions in mitochondrial and metabolic pathways, suggesting that IE2 may contribute to hearing loss through mitochondrial impairment and inflammation. Transmission electron microscopy of cochlear tissues showed severe morphological abnormalities and a marked reduction in mitochondrial number in spiral ganglion neurons (SGNs). Further mechanistic investigation demonstrated that IE2 interacts with TSC2, leading to hyperactivation of mTOR signaling, metabolic dysregulation, and mitochondrial dysfunction. Importantly, administration of mTOR inhibitors substantially alleviated IE2-induced auditory deficits, hair cell degeneration, and neuronal atrophy. These findings identify IE2 through TSC2-mTOR-mediated mitochondrial dysfunction, metabolic reprogramming, and neuroinflammation leading to SNHL. Our study reveals a previously unrecognized mechanism linking IE2 protein expression to auditory neurodegeneration and suggests mTOR modulation as a potential therapeutic strategy for congenital HCMV infection and associated hearing loss.

Keywords:  Human cytomegalovirus; Immediate early protein IE2; Metabolic disorder; Mitochondrial dysfunction; Neuroinflammation; Rapamycin; Sensorineural hearing loss; mTOR signaling

DOI:  https://doi.org/10.1186/s12974-025-03646-6