bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2025–05–04
fifteen papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Metabolic interference impairs influenza A virus replication by dampening vRNA synthesis.
  2. Chikungunya Replication and Infection Is Dependent upon and Alters Cellular Hexosylceramide Levels in Vero Cells.
  3. Investigating how dengue virus-induced metabolic changes affect the host immune response and how to develop Immunomodulatory strategies.
  4. The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions.
  5. A portrait of the infected cell: how SARS-CoV-2 infection reshapes cellular processes and pathways.
  6. Mitofusin-Mediated Mitochondrial Fusion Inhibits Pseudorabies Virus Infection in Porcine Cells.
  7. Effects of oxidative stress on viral infections: an overview.
  8. Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
  9. Metabolism-associated protein network constructing and host-directed anti-influenza drug repurposing.
  10. Epstein-Barr Virus-Driven B-Cell Transformation under Germinal Center Hypoxia Requires External Unsaturated Fatty Acids.
  11. Serum metabolomic characteristics of COVID-19 patients co-infection with echovirus.
  12. Model-Based Characterization of the Metabolism of Recombinant Adeno-Associated Virus (rAAV) Production via Human Embryonic Kidney (HEK293) Cells.
  13. Modulation of glucose metabolism and insulin resistance following hepatitis C virus clearance via direct-acting antivirals.
  14. Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.
  15. Stable expression of SARS-CoV-2 envelope viroporin promotes intracellular calcium depletion in human cells: relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation.
  1. Npj Viruses. 2025 Mar 28. 3(1): 22
    Metabolic interference impairs influenza A virus replication by dampening vRNA synthesis.
    Jens Kleinehr, Chiara Robin Bojarzyn, Michael Schöfbänker, Katharina Daniel, Stephan Ludwig, Eike R Hrincius.
      For replication, viruses exploit the host cell metabolism for biosynthesis of viral components. Recently, we could show that inhibition of glycolysis interfered with IAV replication by impairing the regulation of the viral polymerase as a transcriptase or replicase. Here, we investigated how IAV replication and polymerase regulation is influenced by other metabolic pathways which are directly or indirectly linked to glycolysis. Therefore, we inhibited glutaminolysis, fatty acid synthesis (FAS), oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway (PPP). Inhibition of these metabolic pathways led to a significant reduction of viral titers. Furthermore, the inhibition of glutaminolysis, FAS and OXPHOS unbalanced the cellular glycolysis and respiration network leading to a prolonged phase of viral transcription while replication was strongly decreased. Our data indicate that affecting the cellular glycolysis and respiration balance impairs the dynamic regulation of the viral polymerase, resulting in reduced synthesis of viral genomic RNA and viral particles.
    DOI:  https://doi.org/10.1038/s44298-025-00090-4
  2. Viruses. 2025 Mar 31. pii: 509. [Epub ahead of print]17(4):
    Chikungunya Replication and Infection Is Dependent upon and Alters Cellular Hexosylceramide Levels in Vero Cells.
    Joseph Thomas Noble, Kingsley Bimpeh, Michael Anthony Pisciotta, Judith Mary Reyes Ballista, Kelly Marie Hines, Melinda Ann Brindley.
      Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes significant global morbidity, including fever, rash, and persistent arthralgia. Utilizing untargeted lipidomics, we investigated how CHIKV infection alters host cell lipid metabolism in Vero cells. CHIKV infection induced marked catabolism of hexosylceramides, reducing their levels while increasing ceramide byproducts. Functional studies revealed a reliance on fatty acid synthesis, β-oxidation, and glycosphingolipid biosynthesis. Notably, inhibition of uridine diphosphate glycosyltransferase 8 (UGT8), essential for galactosylceramide production, significantly impaired CHIKV replication and entry in Vero cells. Sensitivity of CHIKV to UGT8 inhibition was reproduced in a disease-relevant cell line, mouse hepatocytes (Hepa1-6). CHIKV was also sensitive to evacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, though the mechanism of inhibition appeared independent of CETP itself, suggesting an off-target effect. These findings highlight specific lipid pathways, particularly glycosphingolipid metabolism, as critical for CHIKV replication and further refine our understanding of how CHIKV exploits host lipid networks. This study provides new insights into CHIKV biology and suggests that targeted investigation of host lipid pathways may inform future therapeutic strategies.
    Keywords:  alphavirus; chikungunya virus; fatty acid synthesis; hexosylceramide; lipidomics
    DOI:  https://doi.org/10.3390/v17040509
  3. Virol J. 2025 Apr 25. 22(1): 117
    Investigating how dengue virus-induced metabolic changes affect the host immune response and how to develop Immunomodulatory strategies.
    Fatemeh Amini Chermahini, Pooria Mohammadi Arvejeh, Francesco M Marincola, Sajjad Ahmad, Ramtin Naderian, Omid Pajand, Majid Eslami, Maliheh Hasannia, Samira Sanami.
      Dengue virus (DENV) infection imposes a significant global health burden, driven by its ability to manipulate host cellular processes to facilitate replication and evade immune defenses. This review explores the complex interplay between DENV, host immunometabolism, and signaling pathways. DENV induces metabolic reprogramming, including glycolytic upregulation, lipid droplet utilization through lipophagy, and alterations in amino acid metabolism, to fulfill its energy and biosynthetic needs. The virus also disrupts mitochondrial dynamics, leading to increased reactive oxygen species (ROS) production, which modulates immune responses but may also contribute to oxidative stress and severe pathology. Concurrently, DENV hijacks host signaling pathways, including PI3K/Akt, NF-κB, and JAK/STAT, to suppress apoptosis, evade type I interferon responses, and drive pro-inflammatory cytokine production. The interplay between these signaling and metabolic pathways highlights a dual role of host processes: enabling viral replication while activating antiviral immune responses. The review also examines potential therapeutic strategies targeting metabolic and signaling pathways to combat DENV infection, including glycolysis inhibitors, lipid metabolism modulators, and host-directed therapies. While significant progress has been made in understanding DENV-induced immunometabolism, further research is needed to elucidate the precise molecular mechanisms and translate these findings into clinical applications. This study underscores the importance of integrating metabolic and signaling insights to identify novel therapeutic targets against DENV and related flaviviruses, addressing the critical need for effective antiviral interventions.
    Keywords:  DENV; Immune response; Metabolic pathway; Viral infection
    DOI:  https://doi.org/10.1186/s12985-025-02745-3
  4. Npj Viruses. 2024 Jun 21. 2(1): 24
    The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions.
    Marijke Verhaegen, Kurt Vermeire.
      Dengue virus (DENV) is the most prevalent arthropod-borne flavivirus and imposes a significant healthcare threat worldwide. At present no FDA-approved specific antiviral treatment is available, and the safety of a vaccine against DENV is still on debate. Following its entry into the host cell, DENV takes advantage of the cellular secretory pathway to produce new infectious particles. The key organelle of the host cell in DENV infections is the endoplasmic reticulum (ER) which supports various stages throughout the entire life cycle of flaviviruses. This review delves into the intricate interplay between flaviviruses and the ER during their life cycle with a focus on the molecular mechanisms underlying viral replication, protein processing and virion assembly. Emphasizing the significance of the ER in the flavivirus life cycle, we highlight potential antiviral targets in ER-related steps during DENV replication and summarize the current antiviral drugs that are in (pre)clinical developmental stage. Insights into the exploitation of the ER by DENV offer promising avenues for the development of targeted antiviral strategies, providing a foundation for future research and therapeutic interventions against flaviviruses.
    DOI:  https://doi.org/10.1038/s44298-024-00031-7
  5. Npj Viruses. 2024 Dec 17. 2(1): 66
    A portrait of the infected cell: how SARS-CoV-2 infection reshapes cellular processes and pathways.
    Valentina Marano, Štěpánka Vlachová, Sofia Maria Luigia Tiano, Mirko Cortese.
      Positive-sense single-stranded RNA (+ssRNA) viruses exert a profound influence on cellular organelles and metabolic pathway by usurping host processes to promote their replication. In this review, we present a portrait of selected cellular pathways perturbed in SARS-CoV-2 infection: the effect of viral translation, replication and assembly on the morphology and function of the ER, the remodelling of degradative pathways with a focus on the autophagic processes, and the alterations affecting cellular membranes and lipid metabolism. For each of these cellular processes, we highlight the specific viral and host factors involved and their interplay in this microscopic tug-of-war between pro-viral and anti-viral effects that ultimately tip the scale toward the propagation or the resolution of the infection.
    DOI:  https://doi.org/10.1038/s44298-024-00076-8
  6. Vet Sci. 2025 Apr 15. pii: 368. [Epub ahead of print]12(4):
    Mitofusin-Mediated Mitochondrial Fusion Inhibits Pseudorabies Virus Infection in Porcine Cells.
    Xiuhan Xu, Yuan Zhao, Zhenbang Zhu, Wei Wen, Xiangdong Li.
      Background: Mitochondria are highly dynamic organelles that undergo fusion/fission dynamics, and emerging evidence has established that mitochondrial dynamics plays a crucial regulatory role in the process of viral infection. Nevertheless, the function of mitochondria dynamics during pseudorabies (PRV) infection remains uncertain. Methods: Our investigation commenced with examining PRV-induced alterations in mitochondrial dynamics, focusing on morphological changes and the expression levels of fusion/fission proteins. We then restored mitochondrial dynamics through Mfn1 (Mitofusin 1)/Mfn2 (Mitofusin 2) overexpression and mdivi-1 (mitochondrial division inhibitor-1) treatment to assess their impact on PRV replication and mitochondrial damage. Results: We found a downregulation of the mitochondrial fusion proteins Mfn1, Mfn2, and OPA1 (optic atrophy 1), along with the activation of the fission protein Drp-1 (dynamin-related protein 1) upon PRV infection. Restoring the function of mitochondrial fusion inhibited PRV infection. Furthermore, elevated mitochondrial membrane potential (MMP), decreased reactive oxygen species (ROS) levels, and an increased mitochondrial number were observed after overexpressing Mfns or treatment with mdivi-1. Conclusions: PRV infection impairs mitochondrial dynamics by altering mitochondrial fusion and fission proteins, and the promotion of Mfn-mediated mitochondrial fusion inhibits PRV replication.
    Keywords:  mitochondrial dynamics; mitochondrial fusion; mitofusin proteins; pseudorabies virus
    DOI:  https://doi.org/10.3390/vetsci12040368
  7. Npj Viruses. 2025 Apr 12. 3(1): 27
    Effects of oxidative stress on viral infections: an overview.
    Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara.
      Viral infections can trigger increased reactive oxygen species (ROS) production and a reduced antioxidant response in the host, leading to redox stress, inflammation, apoptosis, and ultimately, cell and tissue damage, which contribute to disease development. A better understanding of how ROS contributes to viral pathogenesis is critical for the development of novel therapeutic interventions. In this review, we discuss the current knowledge on ROS production and its effects across various viral infections, including severe acute respiratory syndrome-coronavirus-2, influenza A virus, dengue virus, Zika virus, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus infections, to improve future therapeutic and preventive strategies for these infections.
    DOI:  https://doi.org/10.1038/s44298-025-00110-3
  8. mBio. 2025 Apr 29. e0064925
    Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
    Youliang Rao, Chao Qin, Bianca Espinosa, Ting-Yu Wang, Shu Feng, Ali Can Savas, Jill Henley, Lucio Comai, Chao Zhang, Pinghui Feng.
      Despite the global impact caused by the most recent SARS-CoV-2 pandemic, our knowledge of the molecular underpinnings of its highly infectious nature remains incomplete. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. In addition to catalyzing CTP synthesis, CTPS1 also deamidates interferon regulatory factor 3 (IRF3) to dampen interferon induction. Screening a SARS-CoV-2 expression library, we identified several viral proteins that interact with CTPS1. Functional analyses demonstrate that ORF8 and Nsp8 activate CTPS1 to deamidate IRF3 and negate IFN induction, whereas ORF7b and ORF8 activate CTPS1 to promote CTP synthesis. These results highlight CTPS1 as a signaling node that integrates cellular metabolism and innate immune response. Indeed, small-molecule inhibitors of CTPS1 deplete CTP and boost IFN induction in SARS-CoV-2-infected cells, thus effectively impeding SARS-CoV-2 replication and pathogenesis in mouse models. Our work uncovers an intricate mechanism by which a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means to develop antiviral therapy against highly mutagenic viruses.IMPORTANCEOur understanding of the underpinnings of highly infectious SARS-CoV-2 is rudimentary at best. We report here that SARS-CoV-2 activates CTPS1 to promote CTP synthesis and suppress IFN induction, thus coupling immune evasion to activated nucleotide synthesis. Inhibition of the key metabolic enzyme not only depletes the nucleotide pool but also boosts host antiviral defense, thereby impeding SARS-CoV-2 replication. Targeting cellular enzymes presents a strategy to counter the rapidly evolving SARS-CoV-2 variants.
    Keywords:  CTPS1; SARS-CoV-2; antiviral pharmacology; interferon; pyrimidine metabolism
    DOI:  https://doi.org/10.1128/mbio.00649-25
  9. Brief Bioinform. 2025 May 01. pii: bbaf163. [Epub ahead of print]26(3):
    Metabolism-associated protein network constructing and host-directed anti-influenza drug repurposing.
    Hao Tang, Feng Jiang, Zhi Zhang, Jiaojiao Yang, Lu Li, Qingye Zhang.
      Host-directed antivirals offer a promising strategy for addressing the challenge of viral resistance. Virus-host interactions often trigger stage-specific metabolic reprogramming in the host, and the causal links between these interactions and virus-induced metabolic changes provide valuable insights for identifying host targets. In this study, we present a workflow for repurposing host-directed antivirals using virus-induced protein networks. These networks capture the dynamic progression of viral infection by integrating host proteins directly interacting with the virus and enzymes associated with significantly altered metabolic fluxes, identified through dual-species genome-scale metabolic models. This approach reveals numerous hub nodes as potential host targets. As a case study, 50 approved drugs with potential anti-influenza virus A (IVA) activity were identified through eight stage-specific IVA-induced protein networks, each comprising 699-899 hub nodes. Lisinopril, saxagliptin, and gliclazide were further validated for anti-IVA efficacy in vitro through assays measuring the inhibition of cytopathic effects and viral titers in A549 cells infected with IVA PR8. This workflow paves the way for the rapid repurposing of host-directed antivirals.
    Keywords:  genome-scale metabolic models; host-directed antivirals; influenza virus–host interactions; metabolic reprogramming; protein–protein interaction networks
    DOI:  https://doi.org/10.1093/bib/bbaf163
  10. Res Sq. 2025 Apr 24. pii: rs.3.rs-6506954. [Epub ahead of print]
    Epstein-Barr Virus-Driven B-Cell Transformation under Germinal Center Hypoxia Requires External Unsaturated Fatty Acids.
    Larissa Havey, Haixi You, John M Asara, Yin Wang, Rui Guo.
      Epstein-Barr virus (EBV) contributes to over 200,000 cancers annually, predominantly aggressive lymphomas originating from hypoxic germinal centers (< 1% O₂). However, conventional models fail to recapitulate the physiologically relevant hypoxic microenvironment which profoundly influences B-cell metabolic remodeling during transformation. Here, we establish an ex vivo model of EBV-driven B-cell transformation under 1% O₂, demonstrating robust transformation and super-enhancer activation of oncogenic regulators, including MYC. Multi-omic analyses reveal distinct metabolic adaptations to hypoxia. Unlike normoxic B-cells, which rely on fatty acid desaturases and oxidation to mitigate lipotoxicity, hypoxically transformed B-cells suppress fatty acid synthesis while upregulating glycerophospholipid metabolism and lipid droplet formation to buffer excess saturated lipids. Consequently, these cells exhibit heightened dependence on external unsaturated fatty acids to support proliferation. Our findings provide the first physiologically relevant ex vivo model of EBV-driven B-cell transformation under hypoxia, uncovering metabolic vulnerabilities that could inform targeted therapeutic strategies for EBV-associated malignancies.
    DOI:  https://doi.org/10.21203/rs.3.rs-6506954/v1
  11. Virulence. 2025 Dec;16(1): 2497907
    Serum metabolomic characteristics of COVID-19 patients co-infection with echovirus.
    Chunhua Wang, Tingyu Yu, Ying Xia, Feng Tao, Jiali Sun, Jianzhong Zhao, Xiaogang Mao, Mengjun Tang, Lijuan Yin, Yang Yang, Wenjie Tan, Liang Shen, Shuaijie Zhang.
      Currently, the Omicron variant of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to circulate globally. In our multiplex respiratory pathogen detection, we identified numerous instances of co-infection with Echovirus (ECHO) among Coronavirus Disease 2019 (COVID-19) patients, which exacerbated the clinical symptoms of these patients. Such co-infections are likely to impact the subsequent medical treatment. To date, there are no reports on the pathogenic mechanisms related to COVID-19 co-infected with ECHO. Therefore, this study employed the TM Widely-Targeted metabolomics approach to analyze the serum metabolomes of COVID-19 patients with single SARS-CoV-2 infection (COVID-19), COVID-19 patients co-infected with ECHO (COVID-19  +  ECHO), and healthy individuals (Control) recruited from routine physical examinations during the same period. Concurrent clinical laboratory tests were performed on the patients to reveal the differences in metabolomic characteristics between the COVID-19 patients and the COVID-19  +  ECHO patients, as well as to explore potential metabolic pathways that may exacerbate disease progression. Our findings indicate that both clinical examination indicators and the pathways enriched by differential metabolites confirm that patients with dual infection exhibit higher inflammatory and immune responses compared to those with single COVID-19 infections. This difference is likely reflected through abnormalities in the glycerophospholipid metabolic pathway, with the metabolite Sn-Glycero-3-Phosphocholine playing a crucial role in this process. Finally, we established a diagnostic model based on logistic regression using five differential metabolites, which accurately differentiates between the dual infection population and the single COVID-19 infection population (AUC = 0.828).
    Keywords:  SARS-CoV-2; co-infection; echovirus; serum metabolites
    DOI:  https://doi.org/10.1080/21505594.2025.2497907
  12. Bioengineering (Basel). 2025 Mar 27. pii: 345. [Epub ahead of print]12(4):
    Model-Based Characterization of the Metabolism of Recombinant Adeno-Associated Virus (rAAV) Production via Human Embryonic Kidney (HEK293) Cells.
    Somaiyeh Khodadadi Karimvand, Miroslava Cuperlovic-Culf, Amine A Kamen, Miodrag Bolic.
      In this paper, we present a kinetic-metabolic model describing adeno-associated virus (AAV) production via HEK293 cells that encompasses the main metabolic pathways, namely, glycolysis, tricarboxylic acid cycle (TCA), pyruvate fates, the pentose phosphate pathway, anaplerotic reaction, amino acid metabolism, nucleotides synthesis, biomass synthesis, and the metabolic pathways of protein synthesis of the AAV (capsid and Rep proteins). For the modeling, Michaelis-Menten kinetics was assumed to define the metabolic model. A dataset from bioreactor cultures containing metabolite profiles of adeno-associated virus 6 (AAV6) production via triple transient transfection in a low-cell-density culture, including the concentration profiles of glutamine, glutamic acid, glucose, lactate, and ammonium, was utilized for fitting and computing the model parameters. The model that resulted from the adjusted parameters defined the experimental data well. Subsequently, a Sobol-based global sensitivity analysis procedure was applied to determine the most sensitive parameters in the final model.
    Keywords:  Michaelis–Menten kinetics; adeno-associated viruses; global sensitivity analysis; metabolic model; model fitting; optimization
    DOI:  https://doi.org/10.3390/bioengineering12040345
  13. Sci Rep. 2025 Apr 26. 15(1): 14663
    Modulation of glucose metabolism and insulin resistance following hepatitis C virus clearance via direct-acting antivirals.
    Sajida Jabeen, Ramsha Khan, May M Alrashed, Sajjad Ullah, Ghulam Nabi, Malik Ihsan Ullah, Ahmed Bilal Waqar, Kotb A Attia, Itoh Kimiko.
      The positive sense RNA virus, hepatitis C virus (HCV), is affiliated with the Flaviviridae family. Approximately 1% of people around the globe experience the impact of the HCV, which can coax them into potentially fatal conditions, including cirrhosis and carcinoma. The second-highest hepatitis C infection burden lies in Pakistan. The case of a HCV-infected patient who additionally has obesity or concurrent medical conditions like diabetes, HBV infection, or HIV infection is susceptible to becoming direr. Direct-acting antiviral medications replaced interferons as a staple of the treatment plan since they have fewer, milder side effects and a higher SVR rate in patients. The present study sought to assess the modifications to glucose homeostasis in non-diabetic chronic HCV-infected patients getting DAA treatment and the factors that independently pertain to insulin resistance. The study enrolled 250 patients, with 190 individuals having HCV-positive PCR results. The analysis included CBC, LFTs, glycaemic and insulin measurements, and the insulin resistance index calculation. Key cardiometabolic risk factors crucial for defining MASLD were assessed, including BMI measurement, evaluation of type 2 diabetes, and lipid profile analysis. The same tests were repeated following DAA therapy, and HOMA-IR was computed to compare pre-and post-treatment results. Among the 250 recruited patients, 190 were detected as HCV positive by the PCR assay, 57% (110 patients) were women, 43% (80 patients) were men, and patients were 47 years old on average. The patients showed high BMI (average 26.28 kg/m2) and signs of severe insulin resistance (HOMA-IR > 2.5). Multivariable logistic regression analysis pointed out that elevated baseline levels of triglycerides, ALT, ALP, cholesterol, and total bilirubin were independently associated with high insulin resistance. A notable improvement in HOMA-IR from 13.63 ± 2.63 to 3.16 ± 1.52 (p < 0.005) was spotted after administering interferon-free antiviral therapy for 3 months. The presence of high BMI, hyperlipidemia, and elevated levels of ALP, ALT, and AST in non-diabetic HCV-infected patients were independently associated with IR. In patients who previously had a higher IR index, there was a decrease in the HOMA-IR index after infection clearance by direct-acting antivirals.
    Keywords:  DAAs; HOMA-IR; Insulin resistance; SVR; Type-II diabetes mellitus
    DOI:  https://doi.org/10.1038/s41598-025-97827-1
  14. Int Immunopharmacol. 2025 Apr 28. pii: S1567-5769(25)00689-7. [Epub ahead of print]157 114699
    Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.
    Carla Tomatis, Nancy Charo, María F Ferrer, Silvia Aquila, Federico Fuentes, María L Scalise, Mara C A M Aguiar, Gabriel Valdivieso, Eugenio A Carrera Silva, Ricardo M Gómez.
      It has been emphasized that mitochondria play a fundamental role not only in cellular bioenergetics but also in the defense against infections. Here, we investigated mitochondrial network dynamics (MND) and IFN-Iβ signaling response in epithelial A549 cells after yellow fever virus (YFV) infection. We analyze the MND when only some cells are infected at 1 day post-infection (dpi) and after the spread of viral infection, at 3 dpi. Confocal microscopy and MiNA analysis showed that YFV infection leads to a decrease in the number of branches at 3 dpi and an increase in the length of branches at 1 and 3 dpi, suggesting that mitochondrial fission and fusion occur. Consistent with both processes, we found increased transcription of mitofusin 1 and Drp1 and increased colocalization of mitochondria with Drp1 at 3 dpi. In addition, mitochondrial membrane polarization decreased, mtROS production increased, p62 expression decreased, and LC3 expression increased, suggesting an increase in mitophagy flux. We found decreased expression of the IFN inducers RIG-I and MAVS sensors in YFV-infected A549 cells a t 3 dpi. Surprisingly, increased IFN-Iβ levels were observed at transcriptional and protein levels along with IRF7 induction at 1 and 3 dpi. Using the blocking antibody against TLR2, we showed that IFN-Iβ and IL-6 synthesis is maintained by TLR2 signaling. Mechanistically, infection led to activation of the NFκB pathway by degradation of IkBα, and increased phosphorylation of P65 and ERK MAPK signaling. Our results show that YFV infection induces altered MND in epithelial cells and triggers TLR2 signaling.
    Keywords:  A549 cells; IFN-I; Mitochondrial network dynamics; Mitophagy; TLR2; Yellow fever virus
    DOI:  https://doi.org/10.1016/j.intimp.2025.114699
  15. Cell Calcium. 2025 Apr 18. pii: S0143-4160(25)00041-7. [Epub ahead of print]128 103032
    Stable expression of SARS-CoV-2 envelope viroporin promotes intracellular calcium depletion in human cells: relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation.
    Cesare Sala, Andrea Ninu, Valentina Balducci, Giada Allegro, Alberto Montalbano, Matteo Lulli, Martina Lucia Boccitto, Elena Guzzolino, Valentina Spinelli, Annarosa Arcangeli, Laura Sartiani, Elisabetta Cerbai.
      SARS-CoV-2 infection affects the respiratory system but also many tissues and organs that may be adversely compromised. Accordingly, recent evidence has assessed virus ability to infect different cell phenotypes, translate viral proteins and promote virus replication. Among them, Envelope (E) proteins sustain virus replication, promote inflammatory processes and remodelling of host cells. However, despite advances on structure and sequence, E-protein specific location and effects in human host cells are still controversial and poorly investigated. Using lentiviral vectors, we established HEK293 and hiPS cell lines stably expressing E-protein. Immunocytochemistry showed E-protein mainly locates within the endoplasmic reticulum, the ERGIC and the Golgi compartments, while only HEK293 cells display some protein staining in cell periphery suggesting a possible insertion into the plasmalemma. Electrophysiological recordings in HEK293 cells revealed E-protein self-assembles in the plasma membrane to mediate a cation efflux pore that is sensitive to amantadine blockade. Calcium fluorescence imaging in HEK293 and hiPS cells demonstrated E-protein expression induces a marked depletion of thapsigargin-sensitive intracellular calcium stores. The altered calcium homeostasis associates to reduced cell metabolic activity, mitochondrial potential, proliferation rate and promotes ER stress. Finally, trilineage differentiation of hiPS cells indicated E-protein expression preserves cell pluripotency while selectively impairs mesodermal differentiation. These results unveil a critical role of stable E-viroporin expression that through alteration of ER Ca²⁺ homeostasis, metabolic activity and induction of ER stress affects important cellular functions, including the differentiative process from pluripotent to mesodermal progenitors, a critical cell population in self-repair and homeostasis of most human tissue and organs.
    Keywords:  Ca(2+) handling 4; Dysfunctional mitochondria 6; ER stress 5; Envelope 2; SARS-CoV-2 1; Tri-lineage differentiation 7; hiPS cells
    DOI:  https://doi.org/10.1016/j.ceca.2025.103032
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