bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024–07–28
thirteen papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Ginsenoside Rg5, a potent agonist of Nrf2, inhibits HSV-1 infection-induced neuroinflammation by inhibiting oxidative stress and NF-κB activation.
  2. Avian Coronavirus Infectious Bronchitis Virus Activates Mitochondria-Mediated Apoptosis Pathway and Affects Viral Replication by Inducing Reactive Oxygen Species Production in Chicken HD11 Cells.
  3. Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.
  4. Adenosine Triphosphate Release From Influenza-Infected Lungs Enhances Neutrophil Activation and Promotes Disease Progression.
  5. Melatonin Rescues Influenza A Virus-Induced Cellular Energy Exhaustion via OMA1-OPA1-S in Acute Exacerbation of COPD.
  6. Immunometabolites in viral infections: Action mechanism and function.
  7. Japanese encephalitis virus infection causes reactive oxygen species-mediated skeletal muscle damage.
  8. Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis.
  9. Metabolomics and Multi-Omics Determination of Potential Plasma Biomarkers in PRV-1-Infected Atlantic Salmon.
  10. ROS Induced by Aphrocallistes vastus Lectin Enhance Oncolytic Vaccinia Virus Replication and Induce Apoptosis in Hepatocellular Carcinoma Cells.
  11. Proprotein Convertase Subtilisin/Kexin Type 9 Induction in COVID-19 Is Poorly Associated with Disease Severity and Cholesterol Levels.
  12. Preliminary Study on the Restoration of the Phospholipid Profile in Serum from Patients with COVID-19 by Treatment with Vitamin E.
  13. SARS-CoV-2 Infection Positively Correlates with Hyperglycemia and Inflammatory Markers in COVID-19 Patients: A Clinical Research Study.
  1. J Ginseng Res. 2024 Jul;48(4): 384-394
    Ginsenoside Rg5, a potent agonist of Nrf2, inhibits HSV-1 infection-induced neuroinflammation by inhibiting oxidative stress and NF-κB activation.
    Buyun Kim, Young Soo Kim, Wei Li, Eun-Bin Kwon, Hwan-Suck Chung, Younghoon Go, Jang-Gi Choi.
       Background: Herpes simplex virus type 1 (HSV-1), known to latently infect the host's trigeminal ganglion, can lead to severe herpes encephalitis or asymptomatic infection, potentially contributing to neurodegenerative diseases like Alzheimer's. The virus generates reactive oxygen species (ROS) that significantly impact viral replication and induce chronic inflammation through NF-κB activation. Nuclear factor E2-related factor 2 (Nrf2), an oxidative stress regulator, can prevent and treat HSV-1 infection by activating the passive defense response in the early stages of infection.
    Methods and results: Our study investigated the antiviral effects of ginsenoside Rg5, an Nrf2 activator, on HSV-1 replication and several host cell signaling pathways. We found that HSV-1 infection inhibited Nrf2 activity in host cells, induced ROS/NF-κB signaling, and triggered inflammatory cytokines. However, treatment with ginsenoside Rg5 inhibited ROS/NF-κB signaling and reduced inflammatory cytokines through NRF2 induction. Interestingly, the Nrf2 inhibitor ML385 suppressed the expression of NAD(P)H quinone oxidoreductase 1(NQO1) and enhanced the expression of KEAP1 in HSV-1 infected cells. This led to the reversal of VP16 expression inhibition, a protein factor associated with HSV-1 infection, thereby promoting HSV-1 replication.
    Conclusion: These findings suggest for the first time that ginsenoside Rg5 may serve as an antiviral against HSV-1 infection and could be a novel therapeutic agent for HSV-1-induced neuroinflammation.
    Keywords:  Ginsenoside Rg5; Herpes simplex virus type 1; Infection disease; Neuroinflammation; Nuclear factor E2-related factor 2
    DOI:  https://doi.org/10.1016/j.jgr.2024.01.006
  2. Biology (Basel). 2024 Jul 01. pii: 491. [Epub ahead of print]13(7):
    Avian Coronavirus Infectious Bronchitis Virus Activates Mitochondria-Mediated Apoptosis Pathway and Affects Viral Replication by Inducing Reactive Oxygen Species Production in Chicken HD11 Cells.
    Xiaoxiao Han, Yuan Huang, Junli Hao.
      Infectious bronchitis virus (IBV), a coronavirus that causes severe respiratory and gastrointestinal illness in poultry, leads to substantial economic losses. According to earlier research, IBV infection causes chicken macrophage HD11 cells to undergo cell apoptosis. Reactive oxygen species (ROS) and the IBV-activated intrinsic apoptotic signaling pathway were examined in this work. The findings demonstrate that IBV infection causes ROS to accumulate. Moreover, IBV infection decreased the mitochondrial transmembrane potential in HD11 cells, which could be blocked by ROS antioxidants (PDTC and NAC). The two antioxidants significantly affected the expression of Bcl-2 and Bax and further inhibited the activation of caspase-3 and apoptosis in HD11 cells. Additionally, IBV replication was decreased by blocking ROS accumulation. Pretreating HD11 cells with ammonium chloride (NH4Cl) prevented IBV from entering the cells and reduced the oxidative stress which IBV causes. The ability to accumulate ROS was also lost in UV-inactivated IBV. The IBV N protein induces cell apoptosis through the activation of ROS. These findings provide an explanation for the processes of IBV infection in immune cells by indicating that IBV-induced ROS generation triggers cell apoptosis in HD11 cells.
    Keywords:  N protein; apoptosis; chicken HD11 cells; infectious bronchitis virus; reactive oxygen species
    DOI:  https://doi.org/10.3390/biology13070491
  3. Nat Commun. 2024 Jul 26. 15(1): 6311
    Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.
    Lifeng Chen, Jingjing Zhang, Weibin Xu, Jiayi Chen, Yujun Tang, Si Xiong, Yaolan Li, Hong Zhang, Manmei Li, Zhong Liu.
      Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2-LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein-dynactin, PLEKHM1, or HOPS VPS39 to Rab7-RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.
    DOI:  https://doi.org/10.1038/s41467-024-50711-4
  4. J Infect Dis. 2024 Jul 25. 230(1): 120-130
    Adenosine Triphosphate Release From Influenza-Infected Lungs Enhances Neutrophil Activation and Promotes Disease Progression.
    Carola Ledderose, Eleftheria-Angeliki Valsami, Mark Elevado, Wolfgang G Junger.
       BACKGROUND: Adenosine triphosphate (ATP) enhances neutrophil responses, but little is known about the role of ATP in influenza infections.
    METHODS: We used a mouse influenza model to study if ATP release is associated with neutrophil activation and disease progression.
    RESULTS: Influenza infection increased pulmonary ATP levels 5-fold and plasma ATP levels 3-fold vs healthy mice. Adding ATP at those concentrations to blood from healthy mice primed neutrophils and enhanced CD11b and CD63 expression, CD62L shedding, and reactive oxygen species production in response to formyl peptide receptor stimulation. Influenza infection also primed neutrophils in vivo, resulting in formyl peptide receptor-induced CD11b expression and CD62L shedding up to 3 times higher than that of uninfected mice. In infected mice, large numbers of neutrophils entered the lungs. These cells were significantly more activated than the peripheral neutrophils of infected mice and pulmonary neutrophils of healthy mice. Plasma ATP levels of infected mice and influenza disease progression corresponded with the numbers and activation level of their pulmonary neutrophils.
    CONCLUSIONS: Findings suggest that ATP release from the lungs of infected mice promotes influenza disease progression by priming peripheral neutrophils, which become strongly activated and cause pulmonary tissue damage after their recruitment to the lungs.
    Keywords:  ATP release; influenza; mice; neutrophil priming and activation; purinergic signaling
    DOI:  https://doi.org/10.1093/infdis/jiad442
  5. J Pineal Res. 2024 Aug;76(5): e12991
    Melatonin Rescues Influenza A Virus-Induced Cellular Energy Exhaustion via OMA1-OPA1-S in Acute Exacerbation of COPD.
    Yuan-Yuan Wei, Jing-Jing Ye, Da-Wei Zhang, Lei Hu, Hui-Mei Wu, Guang-He Fei.
      Although rapid progression and a poor prognosis in influenza A virus (IAV) infection-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV-induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV-infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV-inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1-dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV-infected pDHBE cells; however, these changes were rescued by OMA1-siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV-induced cellular energy exhaustion via OMA1-OPA1-S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV.
    Keywords:  acute exacerbation of chronic obstructive pulmonary disease; cellular energy exhaustion; glycolysis; influenza A virus; melatonin; metabolic reprogramming; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/jpi.12991
  6. J Med Virol. 2024 Jul;96(7): e29807
    Immunometabolites in viral infections: Action mechanism and function.
    Behnaz Bouzari, Uliana Y Chugaeva, Sajad Karampoor, Rasoul Mirzaei.
      The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.
    Keywords:  antimicrobial defense; immune responses; immunometabolites; metabolism; viral infection
    DOI:  https://doi.org/10.1002/jmv.29807
  7. Eur J Neurosci. 2024 Jul 24.
    Japanese encephalitis virus infection causes reactive oxygen species-mediated skeletal muscle damage.
    Gajendra Singh, Kulwant Singh, Rohit A Sinha, Anjali Singh, Khushi, Alok Kumar.
      Skeletal muscle wasting is a clinically proven pathology associated with Japanese encephalitis virus (JEV) infection; however, underlying factors that govern skeletal muscle damage are yet to be explored. The current study aims to investigate the pathobiology of skeletal muscle damage using a mouse model of JEV infection. Our study reveals a significant increment in viral copy number in skeletal muscle post-JEV infection, which is associated with enhanced skeletal muscle cell death. Molecular and biochemical analysis confirms NOX2-dependent generation of reactive oxygen species, leading to autophagy flux inhibition and cell apoptosis. Along with this, an alteration in mitochondrial dynamics (change in fusion and fission process) and a decrease in the total number of mitochondria copies were found during JEV disease progression. The study represents the initial evidence of skeletal muscle damage caused by JEV and provides insights into potential avenues for therapeutic advancement.
    Keywords:  Autophagy flux inhibition; Japanese encephalitis virus; Mitochondrial dynamics; NOX2 activation; Reactive oxygen species; Skeletal muscle damage
    DOI:  https://doi.org/10.1111/ejn.16469
  8. Rev Med Virol. 2024 Jul;34(4): e2565
    Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis.
    Tianshi Jiang, Kaili Zhu, Guangli Kang, Guojun Wu, Lili Wang, Yurong Tan.
      Global attention is riveted on neurodegenerative diseases due to their unresolved aetiologies and lack of efficacious therapies. Two key factors implicated include mitochondrial impairment and microglial ageing. Several viral infections, including Herpes simplex virus-1 (HSV-1), human immunodeficiency virus (HIV) and Epstein-Barr virus, are linked to heightened risk of these disorders. Surprisingly, numerous studies indicate viruses induce these aforementioned precipitating events. Epstein-Barr virus, Hepatitis C Virus, HIV, respiratory syncytial virus, HSV-1, Japanese Encephalitis Virus, Zika virus and Enterovirus 71 specifically impact mitochondrial function, leading to mitochondrial malfunction. These vital organelles govern various cell activities and, under specific circumstances, trigger microglial ageing. This article explores the role of viral infections in elucidating the pathogenesis of neurodegenerative ailments. Various viruses instigate microglial ageing via mitochondrial destruction, causing senescent microglia to exhibit activated behaviour, thereby inducing neuroinflammation and contributing to neurodegeneration.
    Keywords:  microglia; mitochondria; neurodegenerative disease; neuroinflammation; virus
    DOI:  https://doi.org/10.1002/rmv.2565
  9. Metabolites. 2024 Jul 02. pii: 375. [Epub ahead of print]14(7):
    Metabolomics and Multi-Omics Determination of Potential Plasma Biomarkers in PRV-1-Infected Atlantic Salmon.
    Lada Ivanova, Oscar D Rangel-Huerta, Haitham Tartor, Maria K Dahle, Silvio Uhlig, Christiane Kruse Fæste.
      Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in the plasma of Atlantic salmon (Salmo salar) challenged with Piscine orthoreovirus (PRV-1), aiming to find metabolites associated with the progression of PRV-1 infection into heart and skeletal muscle inflammation (HSMI). The metabolomes of control and PRV-1-infected salmon were compared at three time points during disease development by employing different biostatistical approaches. Targeted metabolomics resulted in the determination of affected metabolites and metabolic pathways, revealing a substantial impact of PRV-1 infection on lipid homeostasis, especially on several (lyso)phosphatidylcholines, ceramides, and triglycerides. Untargeted metabolomics showed a clear separation of the treatment groups at later study time points, mainly due to effects on lipid metabolism pathways. In a subsequent multi-omics approach, we combined both metabolomics datasets with previously reported proteomics data generated from the same salmon plasma samples. Data processing with DIABLO software resulted in the identification of significant metabolites and proteins that were representative of the HSMI development in the salmon.
    Keywords:  Atlantic salmon; Piscine orthoreovirus; biomarkers; biostatistics; lipid metabolism; metabolomics; multi-omics
    DOI:  https://doi.org/10.3390/metabo14070375
  10. Mar Drugs. 2024 Jun 30. pii: 307. [Epub ahead of print]22(7):
    ROS Induced by Aphrocallistes vastus Lectin Enhance Oncolytic Vaccinia Virus Replication and Induce Apoptosis in Hepatocellular Carcinoma Cells.
    Yanan Zhang, Ying Zhu, Gaohui Jiang, Ke Chen, Guohui Zhang, Kan Chen, Ting Ye, Yanrong Zhou, Gongchu Li.
      Oncolytic virotherapy is expected to provide a new treatment strategy for cancer. Aphrocallistes vastus lectin (AVL) is a Ca2+-dependent lectin receptor containing the conserved domain of C-type lectin and the hydrophobic N-terminal region, which can bind to the bird's nest glycoprotein and D-galactose. Our previous studies suggested that the oncolytic vaccinia virus (oncoVV) armed with the AVL gene exerted remarkable replication and antitumor effects in vitro and in vivo. In this study, we found that oncoVV-AVL may reprogram the metabolism of hepatocellular carcinoma cells to promote ROS, and elevated ROS subsequently promoted viral replication and induced apoptosis. This study will provide a new theoretical basis for the application of oncoVV-AVL in liver cancer.
    Keywords:  Aphrocallistes vastus lectin; ROS; oncolytic vaccinia virus
    DOI:  https://doi.org/10.3390/md22070307
  11. Infect Dis Rep. 2024 Jul 17. 16(4): 593-607
    Proprotein Convertase Subtilisin/Kexin Type 9 Induction in COVID-19 Is Poorly Associated with Disease Severity and Cholesterol Levels.
    Patricia Mester, Pablo Amend, Stephan Schmid, Jürgen J Wenzel, Marcus Höring, Gerhard Liebisch, Sabrina Krautbauer, Martina Müller, Christa Buechler, Vlad Pavel.
      SARS-CoV-2 infection was shown to induce proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels in sepsis. Here, we investigate the association between serum PCSK9 levels and disease severity. PCSK9 was measured in serum of 55 controls, 40 patients with moderate and 60 patients with severe COVID-19 disease. Serum PCSK9 was elevated in moderate COVID-19 compared to controls and further increased in severe cases. PCSK9 levels were not associated with C-reactive protein, bacterial superinfections, interventions, or survival in patients with severe COVID-19. PCSK9 regulates circulating cholesterol levels, and 15 cholesteryl ester (CE) species and free cholesterol (FC) were quantified by direct flow injection analysis using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer. Most CE species with shorter fatty acid chains were decreased in severe compared to moderate COVID-19, and none of the CE species were correlated with PCSK9 in patients with severe COVID-19. Levels of all CE species negatively correlated with C-reactive protein in severe COVID-19 patients. Notably, FC was induced in severe compared to moderate COVID-19. The FC/CE ratio correlated positively with inflammatory markers and was associated with non-survival. The current study suggests that the imbalance between CE and FC levels is associated with disease severity and mortality in patients with COVID-19.
    Keywords:  COVID-19; bacterial infection; cholesteryl ester; free cholesterol; intensive care; mortality
    DOI:  https://doi.org/10.3390/idr16040045
  12. Curr Issues Mol Biol. 2024 Jul 08. 46(7): 7219-7238
    Preliminary Study on the Restoration of the Phospholipid Profile in Serum from Patients with COVID-19 by Treatment with Vitamin E.
    María Elena Soto, Linaloe Manzano-Pech, Verónica Guarner-Lans, Adrían Palacios-Chavarría, Rafael Ricardo Valdez-Vázquez, Raúl Martínez-Memije, Mohammed El-Hafidi, Félix Leao Rodríguez-Fierros, Israel Pérez-Torres.
      SARS-CoV-2 is an obligatory intracellular pathogen that requires a lipid bilayer membrane for its transport to build its nucleocapsid envelope and fuse with the host cell. The biological membranes are constituted by phospholipids (PLs), and vitamin E (Vit E) protects them from oxidative stress (OS). The aim of this study was to demonstrate if treatment with Vit E restores the modified profile of the FA in PLs in serum from patients with coronavirus disease-19 (COVID-19). We evaluated Vit E, total fatty acids (TFAs), fatty acids of the phospholipids (FAPLs), total phospholipids (TPLs), 8-isoprostane, thromboxane B2 (TXB2), prostaglandins (PGE2 and 6-keto-PGF1α), interleukin-6 (IL-6), and C-reactive protein (CRP) in serum from 22 COVID-19 patients before and after treatment with Vit E and compared the values with those from 23 healthy subjects (HSs). COVID-19 patients showed a decrease in Vit E, TPLs, FAPLs, and TFAs in serum in comparison to HSs (p ≤ 0.01), and Vit E treatment restored their levels (p ≤ 0.04). Likewise, there was an increase in IL-6 and CRP in COVID-19 patients in comparison with HSs (p ≤ 0.001), and treatment with Vit E decreased their levels (p ≤ 0.001). Treatment with Vit E as monotherapy can contribute to restoring the modified FA profile of the PLs in the SARS-CoV-2 infection, and this leads to a decrease in lipid peroxidation, OS, and the inflammatory process.
    Keywords:  COVID-19; SARS-CoV-2; fatty acids; phospholipids; prostaglandins; vitamin E
    DOI:  https://doi.org/10.3390/cimb46070429
  13. Diseases. 2024 Jul 04. pii: 143. [Epub ahead of print]12(7):
    SARS-CoV-2 Infection Positively Correlates with Hyperglycemia and Inflammatory Markers in COVID-19 Patients: A Clinical Research Study.
    Prashanth Chikkahonnaiah, Siva Dallavalasa, SubbaRao V Tulimilli, Muskan Dubey, Shashidhar H Byrappa, Raghavendra G Amachawadi, SubbaRao V Madhunapantula, Ravindra P Veeranna.
      Diabetes mellitus (DM) is a common comorbidity in COVID-19 subjects. Hyperglycemia at hospital admission identified as a major risk factor and is responsible for poor prognosis. Hematological and inflammatory parameters have been recognized as predictive markers of severity in COVID-19. In this clinical study, we aimed to assess the impact of hyperglycemia at hospital admission on hematological and several inflammatory parameters in COVID-19 patients. A total of 550 COVID-19 subjects were primarily categorized into two major groups (normoglycemic and hyperglycemic) based on random blood sugar levels. On the first day of hospitalization, subjects' oxygen saturation, random blood sugar, hematological variables, and inflammatory parameters were recorded. The hyperglycemic group exhibited higher levels of serum ferritin, total leukocyte count (TLC), lactate dehydrogenase (LDH), neutrophil count, and neutrophil-to-lymphocyte ratio (NLR). In contrast, oxygen saturation and lymphocyte count were lower compared to the normoglycemic group. Significantly elevated levels of hematological variables (TLC, neutrophil count, NLR) and inflammatory parameters (serum ferritin) were observed in the hyperglycemic group. Among inflammatory parameters, only serum ferritin levels showed statistical significance. This study supports the clinical association between hyperglycemia and an increased severity of COVID-19. Consequently, the identification of these parameters is a crucial and valuable prognostic indicator for assessing disease severity in hyperglycemic subjects.
    Keywords:  COVID-19; SARS-CoV-2; hematological variables; hyperglycemia; inflammatory parameters
    DOI:  https://doi.org/10.3390/diseases12070143
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