bims-mevinf 2024-02-11 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–02–11
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.
PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.
Newcastle disease virus infection remodels plasma phospholipid metabolism in chickens.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds with spike protein and inhibits the entry of SARS-CoV-2 into host cells.
Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.
ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection.
Breath Markers of Oxidative Stress in Children with Severe Viral Lower Respiratory Tract Infection.
Tumor Necrosis Factor-α Receptor 1 Mediates Borna Disease Virus 1-Induced Changes in Peroxisomal and Mitochondrial Dynamics in Neurons.

Immunogenetics. 2024 Feb 08.

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.

Ida Florance, Seenivasan Ramasubbu.

  Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.

Keywords:  Autophagy; HIF-1 alpha; Hypoxia; Lipid accumulation; Microglia; Palmitic acid

DOI:  https://doi.org/10.1007/s00251-024-01334-y
J Virol. 2024 Feb 06. e0175123

PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.

Xiaodi Liu, Quanhui Yan, Xueyi Liu, Wenkang Wei, Linke Zou, Feifan Zhao, Sen Zeng, Lin Yi, Hongxing Ding, Mingqiu Zhao, Jinding Chen, Shuangqi Fan.

  Viruses exploit the host cell's energy metabolism system to support their replication. Mitochondria, known as the powerhouse of the cell, play a critical role in regulating cell survival and virus replication. Our prior research indicated that the classical swine fever virus (CSFV) alters mitochondrial dynamics and triggers glycolytic metabolic reprogramming. However, the role and mechanism of PKM2, a key regulatory enzyme of glycolytic metabolism, in CSFV replication remain unclear. In this study, we discovered that CSFV enhances PKM2 expression and utilizes PKM2 to inhibit pyruvate production. Using an affinity purification coupled mass spectrometry system, we successfully identified PKM as a novel interaction partner of the CSFV non-structural protein NS4A. Furthermore, we validated the interaction between PKM2 and both CSFV NS4A and NS5A through co-immunoprecipitation and confocal analysis. PKM2 was found to promote the expression of both NS4A and NS5A. Moreover, we observed that PKM2 induces mitophagy by activating the AMPK-mTOR signaling pathway, thereby facilitating CSFV proliferation. In summary, our data reveal a novel mechanism whereby PKM2, a metabolic enzyme, promotes CSFV proliferation by inducing mitophagy. These findings offer a new avenue for developing antiviral strategies.IMPORTANCEViruses rely on the host cell's material-energy metabolic system for replication, inducing host metabolic disorders and subsequent immunosuppression-a major contributor to persistent viral infections. Classical swine fever virus (CSFV) is no exception. Classical swine fever is a severe acute infectious disease caused by CSFV, resulting in significant economic losses to the global pig industry. While the role of the metabolic enzyme PKM2 (pyruvate dehydrogenase) in the glycolytic pathway of tumor cells has been extensively studied, its involvement in viral infection remains relatively unknown. Our data unveil a new mechanism by which the metabolic enzyme PKM2 mediates CSFV infection, offering novel avenues for the development of antiviral strategies.

Keywords:  AMPK-mTOR; cellular metabolism; classical swine fever virus; mitophagy; pyruvate kinase M2; viral infection

DOI:  https://doi.org/10.1128/jvi.01751-23
iScience. 2024 Feb 16. 27(2): 108962

Newcastle disease virus infection remodels plasma phospholipid metabolism in chickens.

Jun Dai, Xusheng Qiu, Xinyuan Cui, Yiyi Feng, Yuechi Hou, Yingjie Sun, Ying Liao, Lei Tan, Cuiping Song, Weiwei Liu, Yongyi Shen, Chan Ding.

  Newcastle disease is a global problem that causes huge economic losses and threatens the health and welfare of poultry. Despite the knowledge gained on the metabolic impact of NDV on cells, the extent to which infection modifies the plasma metabolic network in chickens remains unknown. Herein, we performed targeted metabolomic and lipidomic to create a plasma metabolic network map during NDV infection. Meanwhile, we used single-cell RNA sequencing to explore the heterogeneity of lung tissue cells in response to NDV infection in vivo. The results showed that NDV remodeled the plasma phospholipid metabolism network. NDV preferentially targets infected blood endothelial cells, antigen-presenting cells, fibroblasts, and neutrophils in lung tissue. Importantly, NDV may directly regulate ribosome protein transcription to facilitate efficient viral protein translation. In conclusion, NDV infection remodels the plasma phospholipid metabolism network in chickens. This work provides valuable insights to further understand the pathogenesis of NDV.

Keywords:  Cell biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.108962
J Innate Immun. 2024 Feb 07.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds with spike protein and inhibits the entry of SARS-CoV-2 into host cells.

Rahul Dilawari, Gaurav Kumar Chaubey, Radheshyam Modanwal, Asmita Dhiman, Sharmila Talukdar, Ajay Kumar, Chaaya Iyengar Raje, Manoj Raje.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by coronavirus-2 (SARS-CoV-2) has emerged as an aggressive viral pandemic. Health care providers confront a challenging task for rapid development of effective strategies to combat this and its long term after effects. Virus entry into host cells involves interaction between receptor-binding domain (RBD) of Spike (S) protein S1 subunit with angiotensin converting enzyme (ACE) present on host cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme involved in cellular glycolytic energy metabolism and micronutrient homeostasis. It is deployed in various cellular compartments and the extra cellular milieu. Though it is known to moonlight as a component of mammalian innate immune defense machinery, till date its role in viral restriction remains unknown.
METHOD: Recombinant S protein, the receptor binding domain (RBD) and human GAPDH protein were used for solid phase binding assays and Biolayer interferometry (BLI). Pseudo virus particles expressing four different strain variants of S protein all harboring ZsGreen gene as marker of infection were used for Flow cytometry-based infectivity assays.
RESULTS: Pseudo-virus entry into target cells in culture was significantly inhibited by addition of human GAPDH into the extracellular medium. Binding assays demonstrated that human GAPDH binds to S protein and RBD domain of SARS-CoV-2 with nano molar affinity.
CONCLUSIONS: Our investigations suggest that this interaction of GAPDH interferes in the viral docking with hACE2 receptors, thereby affecting viral ingress into mammalian cells.

DOI: https://doi.org/10.1159/000535634
J Inflamm Res. 2024 ;17 603-616

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.

Yushan Xu, Miaomiao Li, Mengjiao Lin, Dawei Cui, Jue Xie.

  CD4+ T cells play a critical role in the pathogenesis of viral diseases, which are activated by the internal metabolic pathways encountering with viral antigens. Glutaminolysis converts glutamine into tricarboxylic acid (TCA) circulating metabolites by α-ketoglutaric acid, which is essential for the proliferation and differentiation of CD4+ T cells and plays a central role in providing the energy and structural components needed for viral replication after the virus hijacks the host cell. Changes in glutaminolysis in CD4+ T cells are accompanied by changes in the viral status of the host cell due to competition for glutamine between immune cells and host cells. More recently, attempts have been made to treat tumours, autoimmune diseases, and viral diseases by altering the breakdown of glutamine in T cells. In this review, we will discuss the current knowledge of glutaminolysis in the CD4+ T cell subsets from viral diseases, not only increasing our understanding of immunometabolism but also providing a new perspective for therapeutic target in viral diseases.

Keywords:  CD4+ T cells; glutamine; glutaminolysis; immune response; viral diseases

DOI:  https://doi.org/10.2147/JIR.S443482
Cardiovasc Res. 2024 Feb 03. pii: cvae026. [Epub ahead of print]

ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection.

Clara Bredow, Fabien Thery, Eva Katrin Wirth, Sarah Ochs, Meike Kespohl, Gunnar Kleinau, Nicolas Kelm, Niclas Gimber, Jan Schmoranzer, Martin Voss, Karin Klingel, Joachim Spranger, Kostja Renko, Markus Ralser, Michael Mülleder, Arnd Heuser, Klaus-Peter Knobeloch, Patrick Scheerer, Jennifer Kirwan, Ulrike Brüning, Nikolaus Berndt, Francis Impens, Antje Beling.

   AIMS: Virus infection triggers inflammation and, may impose nutrient shortage to the heart. Supported by type I interferon (IFN) signaling, cardiomyocytes counteract infection by various effector processes, with the IFN-stimulated gene of 15 kDa (ISG15) system being intensively regulated and protein modification with ISG15 protecting mice Coxsackievirus B3 (CVB3) infection. The underlying molecular aspects how the ISG15 system affects the functional properties of respective protein substrates in the heart are unknown.
METHODS AND RESULTS: Based on the protective properties due to protein ISGylation, we set out a study investigating CVB3-infected mice in depth and found cardiac atrophy with lower cardiac output in ISG15-/- mice. By mass spectrometry, we identified the protein targets of the ISG15 conjugation machinery in heart tissue and explored how ISGylation affects their function. The cardiac ISGylome showed a strong enrichment of ISGylation substrates within glycolytic metabolic processes. Two control enzymes of the glycolytic pathway, hexokinase 2 (HK2) and phosphofructokinase muscle form (PFK1), were identified as bona fide ISGylation targets during infection. In an integrative approach complemented with enzymatic functional testing and structural modeling, we demonstrate that protein ISGylation obstructs the activity of HK2 and PFK1. Seahorse-based investigation of glycolysis in cardiomyocytes revealed that, by conjugating proteins, the ISG15 system prevents the infection-/IFN-induced upregulation of glycolysis. We complemented our analysis with proteomics-based advanced computational modeling of cardiac energy metabolism. Our calculations revealed an ISG15-dependent preservation of the metabolic capacity in cardiac tissue during CVB3 infection. Functional profiling of mitochondrial respiration in cardiomyocytes and mouse heart tissue by Seahorse technology showed an enhanced oxidative activity in cells with a competent ISG15 system.
CONCLUSIONS: Our study demonstrates that ISG15 controls critical nodes in cardiac metabolism. ISG15 reduces the glucose demand, supports higher ATP production capacity in the heart, despite nutrient shortage in infection, and counteracts cardiac atrophy and dysfunction.

Keywords:  ISG15; ISGylation; glycolysis; metabolism; mitochondrial function; virus infection

DOI:  https://doi.org/10.1093/cvr/cvae026
Am J Respir Cell Mol Biol. 2024 Feb 05.

Breath Markers of Oxidative Stress in Children with Severe Viral Lower Respiratory Tract Infection.

Thijs A Lilien, Paul Brinkman, Dominic W Fenn, Job B M van Woensel, Lieuwe D J Bos, Reinout A Bem.

  Severe viral lower respiratory tract infection (LRTI), resulting in both acute and long-term pulmonary disease, constitutes a substantial burden among young children. Viral LRTI triggers local oxidative stress pathways by infection and inflammation, and supportive care in the pediatric intensive care unit may further aggravate oxidative injury. The main goal of this exploratory study was to identify and monitor breath markers linked to oxidative stress in children over the disease course of severe viral LRTI. Exhaled breath was sampled during invasive ventilation and volatile organic compounds (VOCs) were analyzed using gas-chromatography and mass-spectrometry. VOCs were selected in an untargeted principal component analysis and assessed for change over time. Additionally, identified VOCs were correlated with clinical parameters. Seventy breath samples from 21 patients were analyzed. A total of 15 VOCs were identified that contributed the most to the explained variance of breath markers. Of these 15 VOCs, 10 were previously linked to pathways of oxidative stress. Eight VOCs, including seven alkanes and methyl alkanes, significantly decreased from the initial phase of ventilation to the day of extubation. No correlation was observed with the administered oxygen dose, while 6 VOCs showed a poor-to-strong positive correlation with driving pressure. In this prospective study of children with severe viral LRTI, the majority of VOCs that were most important for the explained variance mirrored clinical improvement. These breath markers could potentially help monitor the pulmonary oxidative status in these patients, but further research with other objective measures of pulmonary injury is required.

Keywords:  Mechanical Ventilation; Oxidative Stress; Respiratory Syncytial Virus; Respiratory Tract Infection; Volatile Organic Compounds

DOI:  https://doi.org/10.1165/rcmb.2023-0349OC
Int J Mol Sci. 2024 Feb 03. pii: 1849. [Epub ahead of print]25(3):

Tumor Necrosis Factor-α Receptor 1 Mediates Borna Disease Virus 1-Induced Changes in Peroxisomal and Mitochondrial Dynamics in Neurons.

Dominic Osei, Eveline Baumgart-Vogt, Barbara Ahlemeyer, Christiane Herden.

  Borna disease virus 1 (BoDV1) causes a persistent infection in the mammalian brain. Peroxisomes and mitochondria play essential roles in the cellular antiviral immune response, but the effect of BoDV1 infection on peroxisomal and mitochondrial dynamics and their respective antioxidant capacities is still not clear. Using different mouse lines-i.e., tumor necrosis factor-α transgenic (TNFTg; to pro-inflammatory status), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice-we analyzed the abundances of both organelles and their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), in neurons of the hippocampal, cerebral, and cerebellar cortices. In TNFTg mice, a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances was detected; meanwhile, peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). After BoDV1 infection, a strong decrease in mitochondrial (2.1-6.5-fold), SOD2 (2.7-9.1-fold), and catalase (2.7-10.3-fold) abundances, but a slight increase in peroxisomes (1.3-1.6-fold), were detected in Wt and TNFR2ko mice, whereas no changes occurred in TNFR1ko mice. Our data suggest that the TNF system plays a crucial role in the biogenesis of both subcellular organelles. Moreover, TNFR1 signaling mediated the changes in peroxisomal and mitochondrial dynamics after BoDV1 infection, highlighting new mechanisms by which BoDV1 may achieve immune evasion and viral persistence.

Keywords:  Borna disease virus 1; SOD2; TNF; TNFR1; TNFR2; brain; catalase; mitochondria; peroxisomes; persistent infection

DOI:  https://doi.org/10.3390/ijms25031849