bims-mevinf 2025-03-16 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–03–16
twelve papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism.
Dengue Virus and Lipid Metabolism: Unraveling the Interplay for Future Therapeutic Approaches.
Critical role of ferroptosis in viral infection and host responses.
AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.
The depletion of TFAM and p-β-catenin(S552) in mitochondria in response to BoAHV-1 productive infection leads to decreased mitochondrial biogenesis.
PGK1 enhances productive bovine herpesvirus 1 infection by stimulating β-catenin-dependent transcription.
MiR-451a attenuates hepatic steatosis and hepatitis C virus replication by targeting glycerol kinase.
The Essential Role of Mitochondrial Dynamics in Viral Infections.
The CRAC channel inhibitor BTP2 restricts Tulane virus and human norovirus replication independent of store-operated calcium entry.
Effects and potential pathways of goose astrovirus infection on gosling hepatic lipid metabolism.
Regulation of Hepatitis B Virus cccDNA by Metabolic Pathways.
Preclinical evaluation of the efficacy of α-Difluoromethylornithine and Sulindac against SARS-CoV-2 infection.

FEBS J. 2025 Mar 12.

Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism.

Ingrid S de Farias, Guilherme Ribeiro, Isaú H Noronha, Victoria Weise L Lucena, Jean P S Peron, Pedro M Moraes-Vieira, Jose C Alves-Filho, Karina R Bortoluci.

  Zika virus (ZIKV) poses a significant threat due to its association with severe neurological complications, particularly during pregnancy. Although viruses exhibit tropism for neural cells, including astrocytes, the role of these cells in controlling ZIKV replication remains unclear. In this study, we demonstrated that ZIKV induces caspase-1 activation in primary astrocytes despite the absence of classical signs of inflammasome activation. Caspase-1 and caspase-11 double knockout (caspase-1/11-/-) astrocytes exhibit heightened permissiveness to viral replication, accompanied by overactivation of glycolytic metabolism. Inhibition of glycolysis reversed the susceptibility of caspase-1/11-/- astrocytes to ZIKV infection. Protein network analysis revealed mammalian target of rapamycin complex (mTORC) as a link between proteins involved in glycolysis and caspase-1, and mTORC inhibition also suppressed viral replication. Furthermore, we found that the impact of caspase-1/11 on astrocytes depends on the regulation of pyruvate transport to mitochondria for viral replication. Overall, our findings elucidate a caspase-1/11-dependent microbicidal mechanism in astrocytes that involves the mTORC/glycolytic pathway/pyruvate axis, providing insights into potential therapeutic targets for ZIKV infection.

Keywords:  Zika virus; astrocytes; caspase‐1/11; glycolysis; pyruvate

DOI:  https://doi.org/10.1111/febs.70061
Emerg Microbes Infect. 2025 Mar 10. 2477647

Dengue Virus and Lipid Metabolism: Unraveling the Interplay for Future Therapeutic Approaches.

Ying Xie, Li Jiao, Qiangming Sun.

  In recent years, Dengue virus (DENV) has continued to pose significant health risks in tropical and subtropical areas worldwide, raising health alerts worldwide. It can cause hyperviremia in humans and can even lead to fatal clinical diseases. The life cycle of DENV is intricately linked to cellular lipids, and the virus selectively utilizes relevant enzymes involved in lipid metabolism to modulate the existing metabolic system in host cells during entry, replication, assembly, and other stages, thereby creating an environment conducive to its complete replication cycle. At present, there is a lack of effective and specific anti-DENV treatment measures. This review summarizes the recently identified lipid metabolism molecules and metabolic related diseases that affect DENV infection, explores the dependence of DENV on lipid metabolism and provides potential targets for the treatment of dengue fever (DF).

Keywords:  Antiviral; Cholesterol; Dengue virus; Fatty acid; Lipid metabolism; Metabolic disorders; Metabolomics; Phospholipid; Sphingolipid

DOI:  https://doi.org/10.1080/22221751.2025.2477647
Virology. 2025 Mar 08. pii: S0042-6822(25)00097-2. [Epub ahead of print]606 110485

Critical role of ferroptosis in viral infection and host responses.

Qian Mao, Qin Luo, Sheng-Min Ma, Man Teng, Jun Luo.

  Ferroptosis is an iron-dependent form of programmed cell death that plays a crucial role in regulating intracellular redox homeostasis and lipid metabolism, and in combating viral infections. Viruses have persistently evolved and adapted synergistically with their hosts over a long period and, to some extent, have been able to utilize ferroptosis to promote viral replication. Herein, we summarize the characteristics, mechanisms, and regulatory networks of ferroptosis and provide an overview of the key regulatory steps of ferroptosis involved in viral infection, together with the changes in host indicators and key regulatory signaling pathways. This study intends to deepen our understanding of the critical role of ferroptosis in viral infection, which will be meaningful for further revealing the mechanisms underlying the occurrence and progression of virus diseases, as well as for the future exploration of anti-viral strategies.

Keywords:  Anti-viral therapy; Ferroptosis; Host responses; Programmed cell death; Virus

DOI:  https://doi.org/10.1016/j.virol.2025.110485
Cell Mol Life Sci. 2025 Mar 13. 82(1): 111

AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.

Chunling Wang, Xiaoman Liu, Yao Zhao, Shumin Liao, Jiayue Zhang, Yanhong Huang, Yue Shi, Liang Li, Qiuwei Pan, Jian Wu, Yijin Wang.

  Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.

Keywords:  Antiviral medication; Metabolism; TBK1; Viral infection

DOI:  https://doi.org/10.1007/s00018-025-05634-8
Vet Microbiol. 2025 Mar 05. pii: S0378-1135(25)00089-6. [Epub ahead of print]304 110454

The depletion of TFAM and p-β-catenin(S552) in mitochondria in response to BoAHV-1 productive infection leads to decreased mitochondrial biogenesis.

Jiayu Lin, Xiaotian Fu, Xuan Li, Xiuyan Ding, Shitao Li, Filomena Fiorito, Liqian Zhu.

  Varicellovirus bovinealpha (BoAHV) types 1(BoAHV-1) is one of the most significant viruses affecting cattle, causing substantial economic losses in the global cattle industry. Virus productive infection in cell cultures leads to mitochondrial dysfunction, resulting in the overproduction of reactive oxygen species (ROS), which act as inflammatory mediators and exert cytotoxic effects. But the underlying mechanisms remain poorly understood. Mitochondrial transcription factor A (TFAM) is a critical transcriptional activator of the mitochondrial DNA and plays a vital role in mitochondrial biogenesis. In this study, we report that virus acute infection in calves (at 4 days post-infection) increases TFAM protein expression and its accumulation in the peri-nuclear region in a subset of trigeminal ganglia (TG) neurons. Similarly, virus productive infection at later stages in MDBK cells also leads to increased TFAM protein expression and its accumulation in the nucleus. Using TFAM-specific siRNAs, we revealed that TFAM plays a significant role in BoAHV-1 productive infection. Consistent with decreased mitochondrial biogenesis, TFAM protein accumulation in mitochondria was significantly reduced following viral infection, which is corroborated by the reduced accumulation of TOM70 and Tim44 proteins in mitochondria. These proteins are key components of the mitochondrial membrane transport system that facilitates the translocation of TFAM into mitochondria. Interestingly, we found that a subset of β-catenin resides in mitochondria, and viral infection decreases the accumulation of transcriptionally active β-catenin, p-β-catenin(S552), in mitochondria. This may contribute to decreased mitochondrial biogenesis, as the β-catenin-specific inhibitor iCRT14 reduces the protein expression of Cytb, a key regulator of mitochondrial biosynthesis. Collectively, we suggest that the depletion of both TFAM and p-β-catenin(S552) in mitochondria may contribute to the mitochondrial dysfunction induced by BoAHV-1 productive infection.

Keywords:  BoAHV-1; Mitochondria dysfunction; TFAM

DOI:  https://doi.org/10.1016/j.vetmic.2025.110454
Vet Res. 2025 Mar 07. 56(1): 50

PGK1 enhances productive bovine herpesvirus 1 infection by stimulating β-catenin-dependent transcription.

Xuan Li, Wenyuan Gu, Shitao Li, Filomena Fiorito, Xiuyan Ding, Liqian Zhu.

  Bovine herpesvirus 1 (BoHV-1) productive infection stimulates β-catenin-dependent transcription to facilitate virus replication. Phosphoglycerate kinase 1 (PGK1), which catalyses the initial step of ATP production during glycolysis, also has a mitochondrial form that is implicated in tissue injury across various diseases. However, the relationship between BoHV-1 replication and the PGK1 signalling pathway is not yet fully understood. In this study, we discovered that PGK1 signalling significantly influences BoHV-1 replication, with the virus infection leading to a marked increase in the accumulation of PGK1 proteins in mitochondria. Overexpression of β-catenin reduces PGK1 steady-state protein levels while overexpressing PGK1 boosts β-catenin protein expression-a phenomenon that reverses upon virus infection. Importantly, consistent with PGK1's vital role in virus replication, PGK1 stimulates β-catenin-dependent transcriptional activity, partly by promoting the nuclear accumulation of transcriptionally active β-catenin and phospho-β-catenin (S552) in virus-infected cells. In summary, our findings suggest for the first time that PGK1 signalling may be involved in BoHV-1 replication and contribute to virus pathogenicity.

Keywords:  BoHV-1; PGK1; mitochondria; β-Catenin signalling

DOI:  https://doi.org/10.1186/s13567-025-01480-5
J Transl Med. 2025 Mar 13. 23(1): 322

MiR-451a attenuates hepatic steatosis and hepatitis C virus replication by targeting glycerol kinase.

Swagata Majumdar, Deeya Roy Chowdhury, Bidhan Chandra Chakraborty, Abhijit Chowdhury, Simanti Datta, Soma Banerjee.

   BACKGROUND: Lipotoxicity is one of the causes for the progression of fatty liver in chronic hepatitis (CH) towards end-stage liver diseases. The role of miRNAs in the signalling pathways of lipid metabolism has been studied, but their direct targets in this pathway have not been identified yet. Here, we have characterized a downregulated miRNA in CH namely miR-451a, which has a direct impact on the lipid metabolism pathway.
METHODS: Liver tissue samples and blood were collected from CHC/CHB patients and normal individuals. Huh7 and SNU449 cell lines were used for in vitro assays. Expressions of miRNA/mRNAs and proteins were confirmed by qRT-PCR and immuno-blot analysis. Oil Red O staining, Colorimetric, and Fluorometric assay kit were used to quantify triglyceride (TG) and cholesterol from tissue and serum, respectively. Target prediction and pathway analysis were performed using Targetscan, miRWalk, and DAVID respectively. 3'UTR-Luciferase assay and Co-immuno-precipitation were conducted to determine direct interaction between miRNA-mRNA and protein-protein, respectively. Unpaired two-tailed Student's t-test and Mann-Whitney test were employed as required using GraphPad prism. P < 0.05 was considered as significant.
RESULTS: The miRNA, miR-451a was selected as one of the downregulated miRNAs in progressive liver disease stages of CHC and CHB. Target identification and pathway analysis of this miRNA revealed that lipid metabolism pathway gene, glycerol kinase (GK), could be the target of this miRNA. Subsequent 3'UTR Luciferase assay and immuno-blot analysis confirmed the binding of miR-451a to GK. Though both hepatitis viruses, HCV and HBV, could alter the lipid metabolism pathways, intracellular TG and cholesterol content were observed to be significantly higher upon HCV infection only. It also suppressed the expression of miR-451a, resulting in overshooting of GK expression. GK interacted positively with the transcription factor SREBP1, which led to overexpression of Fatty acid synthase, Acetyl- CoA Carboxylase, and Stearoyl-CoA desaturase. As a result, intracellular fatty acids, TG, and cholesterol synthesis and accumulation heightened but trafficking dropped, resulting in hypo-cholesterolemia in blood. While, restoration of miR-451a impeded lipid accumulation, reduced steatohepatitis and suppressed HCV replication as well.
CONCLUSION: These findings suggest that the alteration in the hepatic lipid profile upon HCV/HBV infection is attributed to the downregulation of miR-451a, which has the potential to restrict the expression of GK and SREBP1 in the TG biosynthesis pathway, implying that supplementation of miR-451a may be a potential therapeutic strategy for impeding CHC.

Keywords:  Hepatic steatosis; Hepatitis C virus; Lipid metabolism; miR-451a

DOI:  https://doi.org/10.1186/s12967-025-06286-9
Int J Mol Sci. 2025 Feb 24. pii: 1955. [Epub ahead of print]26(5):

The Essential Role of Mitochondrial Dynamics in Viral Infections.

Xujie Duan, Rui Liu, Wenjing Lan, Shuying Liu.

  Mitochondria are dynamic organelles that play crucial roles in energy production, metabolic balance, calcium homeostasis, apoptosis, and innate immunity, and are key determinants of cell fate. They are also targets for viral invasion of the body. Many viral proteins target mitochondria, controlling mitochondrial morphology, metabolism, and immune response, thereby achieving immune evasion, promoting their proliferation, and accelerating the infection process. Mitochondrial quality control is key to maintaining normal physiological functions and mitochondrial homeostasis. Dysregulation of mitochondrial dynamics is closely related to the development of many diseases. New roles of mitochondrial dynamics in viral infection are constantly being discovered. Viruses change mitochondrial dynamics by targeting mitochondria to achieve a persistent state of infection. Currently, understanding of mitochondrial dynamics during viral infection is limited. Research on the impact of viral proteins on mitochondrial dynamics provides a foundation for investigating the pathogenesis of viral infections, the disease process, and identifying potential therapeutic targets. This review focuses on the connection between viral infection and mitochondrial dynamics and priority areas for research on virus-mediated mitochondrial immunity, provides insight into the regulation of mitochondrial dynamics by viruses targeting mitochondria, and explores potential means of mitochondrial-mediated control and treatment of viral diseases.

Keywords:  apoptosis; innate immunity; mitochondria; mitochondrial dynamics; viral infection

DOI:  https://doi.org/10.3390/ijms26051955
bioRxiv. 2025 Feb 24. pii: 2025.02.23.639787. [Epub ahead of print]

The CRAC channel inhibitor BTP2 restricts Tulane virus and human norovirus replication independent of store-operated calcium entry.

Francesca J Scribano, J Thomas Gebert, Kristen A Engevik, Nicole M Hayes, Son Pham, Soni Kaundal, Janam J Dave, B V Venkataram Prasad, Mary K Estes, Sasirekha Ramani, Joseph M Hyser.

Human norovirus is the leading cause of viral gastroenteritis across all age groups. While there is a need for human norovirus antivirals, therapeutic development has been hindered by a lack of cell culture systems and animal models of infection. Surrogate viruses, such as Tulane virus (TV), have provided tractable systems to screen potential antiviral compounds. Our previous work demonstrated that Tulane virus encodes a viral ion channel, which dysregulates cytosolic calcium signaling. We set out to investigate whether host pathways triggered by viral ion channel activity, including store-operated calcium entry (SOCE), play a role in virus replication. Using pharmacologic inhibitors and genetically engineered cell lines, we establish that the SOCE inhibitor, BTP2, reduces TV replication in an SOCE-independent manner. We observed a significant reduction in TV replication, protein expression, and RNA synthesis in cells with both pre- and post-infection BTP2 treatment. By serial passage and plaque isolation, we demonstrate that TV quasi-species have mixed susceptibility and resistance to BTP2. Sequence comparison of the quasi-species revealed that amino acid changes in the structural proteins were associated with drug resistance. We utilized reverse genetics to generate TV with the resistance-associated VP1 and VP2 amino acid changes and found that a single amino acid change in VP1 (I380M) conferred BTP2 resistance. Further, expression of resistant VP2 alone was sufficient to partially rescue the replication of susceptible virus. Together, this supports that TV structural proteins are the targets of BTP2. Finally, using human intestinal organoids, we demonstrate that BTP2 significantly reduces human norovirus replication.
Importance: Our work identifies BTP2 as a potential human norovirus antiviral pharmacophore and highlights the utility of targeting calicivirus structural proteins to restrict viral replication. Further, we establish a system whereby Tulane virus can be used to screen novel antiviral candidates and establish their mechanism of action. Together, this will facilitate rapid preclinical validation of other novel human norovirus therapeutics.

DOI: https://doi.org/10.1101/2025.02.23.639787
Front Microbiol. 2025 ;16 1531373

Effects and potential pathways of goose astrovirus infection on gosling hepatic lipid metabolism.

Chao Yin, Yun Shi, Haiqin Li, Zhihua Lu, Xiaona Gao, Guoliang Hu, Xiaoquan Guo.

   Introduction: The adverse effects of goose astrovirus (GoAstV) on avian growth and health have been widely reported previously, while the stress reactions and corresponding mechanism of gosling liver responding to GoAstV infection remain not entirely clear.
Methods: One-day-old goslings inoculated subcutaneously with 2 × 10-6 TCID50 of GoAstV were employed as an experimental model, and the potential effects and pathways of GoAstV infection on gosling liver functions were investigated by combining the morphological, biochemical and RNA sequencing (RNA-seq) techniques.
Results: Structural and functional impairments were found in gosling livers post the virus infection, as characterized by the histological alterations in liver index and morphology of hepatic cord and sinuses, as well as the abnormal expression patterns of the cellular antioxidant, inflammation and apoptosis-related genes. RNA sequencing analysis were performed to investigate the underlying mechanism. Results showed that the analysis of screened 1949 differentially expressed genes (DEGs) were mainly enriched in GO terms related to organic immune defense and substance metabolism, and their corresponding KEGG pathways represented by PPAR signaling pathway, intestinal immune network for IgA production, and fatty acid metabolism and degradation, suggesting that the functions of avian immunity and lipid metabolism were greatly changed after the GoAstV infection. Finally, the lipid deposition in gosling hepatocytes were further demonstrated by the subsequent Oil red O staining, biochemical detection of serum TG and HDL-C, and the gene expression analysis including PPARα, PPARγ, ACSBG2, ACSL5, CPT1A and PCK1.
Discussion: Though limitations exist, the findings of this study are helpful to expand our understanding about the negative effects of GoAstV on goslings, and provide us with new clues for the salvaging of GoAstV-induced liver dysfunctions in poultry industry.

Keywords:  astrovirus; gosling; infection; lipid metabolism; liver; pathway

DOI:  https://doi.org/10.3389/fmicb.2025.1531373
Clin Mol Hepatol. 2025 Mar 12.

Regulation of Hepatitis B Virus cccDNA by Metabolic Pathways.

Hyeong-Jin Cho, Sung-Gyoo Park.



Keywords:  GDH1; Hepatitis B virus; Metabolism; cccDNA

DOI:  https://doi.org/10.3350/cmh.2025.0255
bioRxiv. 2025 Feb 28. pii: 2025.02.26.640194. [Epub ahead of print]

Preclinical evaluation of the efficacy of α-Difluoromethylornithine and Sulindac against SARS-CoV-2 infection.

Natalia A Ignatenko, Hien Trinh, April M Wagner, Eugene W Gerner, Christian Bime, Chiu-Hsieh Hsu, David G Besselsen.

Despite numerous research efforts and several effective vaccines and therapies developed against COronaVIrus Disease 2019 (COVID-19), drug repurposing remains an attractive alternative to identify new treatments for SARS-CoV-2 virus variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO) and a non-steroidal anti-inflammatory drug (NSAID) Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA and ACE2 mRNA levels in the infected human cell lines by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The antiviral activity of DFMO and Sulindac was tested in vivo as prophylaxis (drug supplementation at the doses equivalent to the human chemoprevention trial started 7 days before infection) or as treatment (drug supplementation started 24 hours post-infection). Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p=0.01, and p=0.027, respectively), and the combination was effective in the aged male mice (p=0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p=0.001) and DFMO/Sulindac combination (p=0.018), while aged female mice did not benefit significantly from any interventions. The treatment regime was ineffective in suppressing SARS-CoV-2 infection in K18-hACE2 mice. Overall, animal studies demonstrated the protective age- and sex-dependent antiviral efficacy of DFMO and Sulindac against SARS-CoV-2.

DOI: https://doi.org/10.1101/2025.02.26.640194