bims-mevinf 2025-04-20 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–04–20
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Human Cytomegalovirus Infection Reduces an Endogenous Antiviral Fatty Acid by Promoting Host Metabolism.
Analysis of Metabolomic Reprogramming Induced by Infection with Kaposi's Sarcoma-Associated Herpesvirus Using Untargeted Metabolomic Profiling.
Spring viraemia of carp virus modulates the time-dependent unfolded protein response to facilitate viral replication.
High Glucose Reduces Influenza and Parainfluenza Virus Productivity by Altering Glycolytic Pattern in A549 Cells.
Viral manipulation of host cell glutamine metabolism and glutamine rewiring in hepatic diseases: Editorial on "GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome".
HDAC4 suppresses porcine epidemic diarrhea virus infection through negatively regulating MEF2A-GLUT1/3 axis- mediated glucose uptake.
Ebola Virus Glycoprotein Impairs Human Retinal Pigment Epithelial Barrier Function via the PI3K/Akt-Nrf2 Pathway.
Protein-S-nitrosylation of human cytomegalovirus pp65 reduces its ability to undermine cGAS.

bioRxiv. 2025 Mar 31. pii: 2025.03.31.646481. [Epub ahead of print]

Human Cytomegalovirus Infection Reduces an Endogenous Antiviral Fatty Acid by Promoting Host Metabolism.

Yuecheng Xi, Rebekah L Mokry, Nicholas D Armas, Ian Kline, Maxwell Wegner, John G Purdy.

Some viruses, including human cytomegalovirus (HCMV), induce the synthesis of fatty acids and lipids to ensure that the lipid environment of infected cells supports virus replication. HCMV infection broadly reprograms metabolism to ensure central carbon metabolism provides the metabolites required for anabolic synthesis of nucleotides, proteins, and lipids while also meeting the energy demands placed on the infected cells. While HCMV infection increases the levels of most very long chain fatty acids (VLCFA), we found that the levels of erucic acid (EA), a C22:1 monounsaturated VLCFA, are reduced. Treating infected cells with EA disrupted a late step in virus replication, resulting in the release of virions with reduced infectivity. Moreover, we used lipidomics to determine that EA-treated cells had elevated levels of lipids containing a combination of a C22:1 tail and a VLC polyunsaturated fatty acid tail (VLC-PUFA). We demonstrate that fatty acid elongase 5 (ELOVL5) mediated production of VLC-PUFAs is stimulated by HCMV infection. ELOVL5 aided the increase in lipids with C22:1 plus VLC-PUFA tails following EA treatment and reduced the overall level of C22:1 in HCMV-infected cells. Moreover, we found that ELOVL5 mollified EA inhibition of HCMV replication, suggesting ELOVL5 plays a critical role in reducing the level of an endogenous FA with antiviral properties. Our study provides insight into how infection may increase the synthesis of an antiviral metabolite or FA and how the virus may evade their antiviral effect by promoting their metabolism.

DOI: https://doi.org/10.1101/2025.03.31.646481
Int J Mol Sci. 2025 Mar 28. pii: 3109. [Epub ahead of print]26(7):

Analysis of Metabolomic Reprogramming Induced by Infection with Kaposi's Sarcoma-Associated Herpesvirus Using Untargeted Metabolomic Profiling.

Abdulkarim Alfaez, Michael W Christopher, Timothy J Garrett, Bernadett Papp.

  Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus. There are no vaccines or antiviral therapies for KSHV. Identifying the cellular metabolic pathways that KSHV manipulates can broaden the knowledge of how these pathways contribute to sustaining lytic infection, which can be targeted in future therapies to prevent viral spread. In this study, we performed an untargeted metabolomic analysis of KSHV infected telomerase-immortalized gingival keratinocytes (TIGK) cells at 4 h post-infection compared to mock-infected cells. We found that the metabolomic landscape of KSHV-infected TIGK differed from that of the mock. Specifically, a total of 804 differential metabolic features were detected in the two groups, with 741 metabolites that were significantly upregulated, and 63 that were significantly downregulated in KSHV-infected TIGK cells. The differential metabolites included ornithine, arginine, putrescine, dimethylarginine, orotate, glutamate, and glutamine, and were associated with pathways, such as the urea cycle, polyamine synthesis, dimethylarginine synthesis, and de novo pyrimidine synthesis. Overall, our untargeted metabolomics analysis revealed that KSHV infection results in marked rapid alterations in the metabolic profile of the oral epithelial cells. We envision that a subset of these rapid metabolic changes might result in altered cellular functions that can promote viral lytic replication and transmission in the oral cavity.

Keywords:  KSHV; de novo infection; metabolomics; oral epithelial cells

DOI:  https://doi.org/10.3390/ijms26073109
Front Immunol. 2025 ;16 1576758

Spring viraemia of carp virus modulates the time-dependent unfolded protein response to facilitate viral replication.

Alejandro Romero, Antonio Figueras, Beatriz Novoa.

   Introduction: The spring viraemia of carp virus (SVCV) poses a significant threat to global aquaculture, yet effective antiviral drugs and vaccines remain unavailable. Understanding the interplay between host-pathogen interactions and SVCV replication is crucial for devising preventive strategies.
Methods: ZF4 cells were exposed to UV-inactivated SVCV or live SVCV at different multiplicities of infection, and the modulation of the unfolded protein response (UPR) was assayed by qPCR at different times. Moreover, ZF4 cells were treated with several UPR modulators to investigate their effect on viral replication. The UPR was also modulated in vivo in zebrafish larvae, and its impact on the survival against SVCV infection was evaluated.
Results and conclusions: This study reveals how SVCV exploits the host's UPR to facilitate its replication. SVCV targets the immunoglobulin heavy chain-binding protein (BiP) and the activating transcription factor 4 (ATF4) during early infection to enhance viral RNA synthesis and translation. At later stages, activation of the BiP, the PKR-like ER kinase (PERK), and the inositol-requiring enzyme 1 alpha (IRE1α) pathways supports the release of viral progeny and induces cellular processes, including immune responses and apoptotic cell death. Furthermore, the data demonstrate that modulating UPR pathways, particularly ATF6 and PERK, significantly affect viral replication, providing a novel avenue for antiviral drug development. Preliminary in vivo studies suggest the feasibility of chemically modulating the UPR to combat SVCV, though optimizing administration conditions to maximize efficacy while minimizing side effects warrants further investigation. These findings offer critical insights into the molecular mechanisms underlying SVCV pathogenesis and highlight promising targets for therapeutic intervention.

Keywords:  SVCV; antiviral activity; endoplasmic reticulum (ER); immune response; unfolded protein response (UPR); viral infection; viral replication

DOI:  https://doi.org/10.3389/fimmu.2025.1576758
Int J Mol Sci. 2025 Mar 25. pii: 2975. [Epub ahead of print]26(7):

High Glucose Reduces Influenza and Parainfluenza Virus Productivity by Altering Glycolytic Pattern in A549 Cells.

Kareem Awad, Maha Abdelhadi, Ahmed M Awad.

  Influenza A virus is responsible for annual epidemics and occasional pandemics leading to significant mortality and morbidity in human populations. Parainfluenza viruses also contribute to lung infections and chronic lung disease. In this study, we investigated the effect of high glucose on the productivity of influenza A and Sendai (murine parainfluenza type 1) viruses in A549 immortalized cells. A glycolytic pattern of infection was determined by monitoring the release of lactate and phosphofructokinase (PFK) activity in infected and uninfected cells. qRT-PCR was used to analyze the expression of viral and cellular cytokine mRNA levels in cultured cells. The data show that the productivity of both influenza and Sendai viruses was reduced in A549 cells cultured in high-glucose conditions. This was accompanied by increased lactate production and altered PFK activity profile. Endogenous or virus infection-induced interferon β (IFN-β) mRNA expression was significantly decreased in high glucose compared to normal glucose status during early times of infection. Unlike in Sendai virus-infected cells, H1N1 virus reversed the significant increase in transforming growth factor β1 (TGF-β1) mRNA expression due to increased glucose concentration during early infection times. In conclusion, high glucose may have a negative effect on influenza and parainfluenza productivity in vitro. This effect may be considered when evaluating personalized therapeutic/diagnostic markers in infection-accompanied hyperglycemic status.

Keywords:  Sendai virus; TGF-β1; glycolysis; influenza; phosphofructokinase

DOI:  https://doi.org/10.3390/ijms26072975
Clin Mol Hepatol. 2025 Apr 11.

Viral manipulation of host cell glutamine metabolism and glutamine rewiring in hepatic diseases: Editorial on "GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome".

Mehrangiz Dezhbord, Kyun-Hwan Kim.



Keywords:   GDH1; histone methylations; Hepatitis B virus

DOI:  https://doi.org/10.3350/cmh.2025.0366
Vet Microbiol. 2025 Apr 11. pii: S0378-1135(25)00155-5. [Epub ahead of print]305 110520

HDAC4 suppresses porcine epidemic diarrhea virus infection through negatively regulating MEF2A-GLUT1/3 axis- mediated glucose uptake.

Xiaomin Wang, Lei Wang, Duan Li, Yilong Liu, Qi Shang, Yanling Liu, Leyi Zhang, Zheng Xu, Cuiqin Huang, Changxu Song.

  Porcine epidemic diarrhea virus (PEDV), a porcine enteropathogenic coronavirus, causes severe diarrhea and death in neonatal piglets. Histone deacetylase 4 (HDAC4), a member of class IIa deacetylases, controls a wide range of physiological processes, but, little is known about its role in PEDV infection. Here, we report a novel strategy by which PEDV manipulates HDAC4. First, HDAC4 expression was examined, and showed a significant down-regulation in PEDV-infected Vero and IPEC-J2 cells. Subsequently, knockdown of HDAC4 by specific small interfering RNA (siRNA) led to an increase in viral infection, whereas overexpression of HDAC4 remarkably suppressed PEDV infection. Mechanistically, we showed that HDAC4 significantly reduced glucose uptake, as glucose is required for PEDV infection. Through screening, we identified glucose transporters 1 and 3 (GLUT1 and GLUT3) as responsible for glucose uptake during PEDV infection. We further confirmed that HDAC4 regulated GLUT1 and GLUT3 expression through its converging hub, myocyte enhancer factor 2 A (MEF2A). Taken together, these findings contribute to a better understanding of a novel function of HDAC4 in regulating glucose uptake via MEF2A-GLUT1/3 to limit PEDV infection, and provide new strategies for the development of anti-PEDV drugs.

Keywords:  GLUT; Glucose uptake; HDAC4; MEF2A; PEDV; Viral infection

DOI:  https://doi.org/10.1016/j.vetmic.2025.110520
ACS Infect Dis. 2025 Apr 16.

Ebola Virus Glycoprotein Impairs Human Retinal Pigment Epithelial Barrier Function via the PI3K/Akt-Nrf2 Pathway.

Shaoying Chen, Dingzhou Wu, Xiujiao Deng, Qingping Zhan, Zhizhi Pan, Zhuo Chen, Zijia Liu, Chuqing Chen, Yuliu Chen, Lin Li, Shuwen Liu, Suiyi Tan.

  Ebola virus (EBOV) causes deadly Ebola virus disease (EVD), and EVD survivors are at high risk of developing blinding ocular complications, which associate with the breakdown of human retinal pigment epithelial (RPE) barrier. Here, we demonstrated EBOV glycoprotein (GP) could directly impair RPE barrier function. EBOV GP significantly decreased expression of tight junction (TJ) proteins in RPE monolayers, resulting in an increase of monolayer permeability. EBOV GP activated PI3K/Akt pathway and induced oxidative stress in RPE cells as evidenced by an increase in the production of reactive oxygen species (ROS), decreased expression of an antioxidant factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and its downstream proteins heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase (quinone) 1 (NQO1). We found activating Nrf2 could counteract EBOV GP-induced RPE barrier injury. Furthermore, GP2 subunit is the key region in the GP that impairs RPE barrier function. Destruction of RPE barrier function by EBOV GP leads to translocation of bacteria and HIV-1. We confirmed EBOV GP-mediated impairment of RPE barrier function in mice. As an Nrf2 activator, resveratrol displays protective effects on the RPE barrier function. Collectively, our study demonstrates EBOV GP impairs the RPE barrier function through PI3K/Akt-Nrf2 pathway and resveratrol is a promising therapeutic agent for EVD-associated retinal complications.

Keywords:  EBOV glycoprotein; Nrf2; PI3K/Akt; resveratrol; retinal pigment epithelial

DOI:  https://doi.org/10.1021/acsinfecdis.4c01039
J Virol. 2025 Apr 17. e0048125

Protein-S-nitrosylation of human cytomegalovirus pp65 reduces its ability to undermine cGAS.

Justin B Cox, Masatoshi Nukui, Eain A Murphy.

  Post-translational modifications (PTMs) are key regulators of various processes important for cell survival. These modifications are critical for dealing with stress conditions, such as those observed in disease states, and during infections with various pathogens. We previously reported that during infection of primary dermal fibroblasts, multiple human cytomegalovirus (HCMV)-encoded proteins were post-translationally modified by the addition of a nitric oxide group to cysteine residues, a modification called protein-S-nitrosylation. For example, tegument protein pp71 is nitrosylated, diminishing its ability to inhibit STING, a protein necessary for DNA virus immune response. Herein, we report that an additional HCMV tegument protein, pp65, responsible for the inhibition of cGAS is also modified by protein-S-nitrosylation on two cysteine residues. Utilizing site-directed mutagenesis to generate recombinant viruses that encode a pp65 that cannot be protein-S-nitrosylated, we evaluated the impact of this PTM on viral replication and how the virus impacts the cGAS/STING pathway. We report that the nitrosylation of pp65 negatively impacts its ability to block cGAS enzymatic functions. pp65 protein-S-nitrosylation mutants demonstrated a decrease in cGAS/STING-induced IRF3 and TBK1 phosphorylation. Additionally, we observed a reduction in IFN-β1 secretion in NuFF-1 cells expressing a nitrosylation-resistant pp65. We report that HCMV expressing a protein-S-nitrosylation-deficient pp65 is resistant to the activation of cGAS in the infection of primary dermal fibroblasts. Our work suggests that nitrosylation of viral proteins may serve as a broadly neutralizing mechanism in HCMV infection.
IMPORTANCE: Post-translational modifications (PTM) are utilized by host cells to limit an invading pathogen's ability to establish a productive infection. A potent PTM, called protein-S-nitrosylation, has anti-bacterial and anti-viral properties. Increasing protein-S-nitrosylation with the addition of nitric oxide donor compounds reduced HCMV replication in fibroblasts and epithelial cells. We previously reported that protein-S-nitrosylation of HCMV pp71 limits its ability to inhibit STING. Herein, we report that the protein-S-nitrosylation of HCMV pp65 impacts its ability to limit cGAS activity, an additional protein important in regulating interferon response. Therapeutically, patients provided nitric oxide by inhalation reduced viral replication in coronavirus disease 2019, influenza, and even impacted bacterial growth within patients' lungs. It is thought that an increase in free nitric oxide increases the frequency of nitrosylated proteins. Understanding how protein-S-nitrosylation regulates a common DNA virus like HCMV will provide insights into the development of broadly neutralizing therapeutics in drug-resistant viral infections.

Keywords:  HCMV; PTM; STING; cGAS; herpesviruses; pp65; protein-S-nitrosylation

DOI:  https://doi.org/10.1128/jvi.00481-25