bims-mevinf 2024-12-08 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–12–08
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Flaviviruses induce ER-specific remodelling of protein synthesis.
Sample Preparation for Global Metabolic Profiling of Vaccinia Virus-Infected Primary Human Foreskin Fibroblasts.
Newcastle disease virus infection induces parthanatos in tumor cells via calcium waves.
Intrinsic Factors Behind the Long-COVID: V. Immunometabolic Disorders.
Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses.
Untargeted metabolomics and lipidomics in COVID-19 patient plasma reveals disease severity biomarkers.
Reactive oxygen species induced by SARS-CoV-2 infection can induce EMT in solid tumors: Potential role of COVID-19 in chemo-resistance and metastasis.
High glucose potentiates Zika virus induced-astroglial dysfunctions.
Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC).
Oxidative stress indexes as biomarkers of the severity in COVID-19 patients.

PLoS Pathog. 2024 Dec 02. 20(12): e1012766

Flaviviruses induce ER-specific remodelling of protein synthesis.

Ho Him Wong, Dorian Richard Kenneth Crudgington, Lewis Siu, Sumana Sanyal.

Flaviviruses orchestrate a unique remodelling of the endoplasmic reticulum (ER) to facilitate translation and processing of their polyprotein, giving rise to virus replication compartments. While the signal recognition particle (SRP)-dependent pathway is the canonical route for ER-targeting of nascent cellular membrane proteins, it is unknown whether flaviviruses rely on this mechanism. Here we show that Zika virus bypasses the SRP receptor via extensive interactions between the viral non-structural proteins and the host translational machinery. Remarkably, Zika virus appears to maintain ER-localised translation via NS3-SRP54 interaction instead, unlike other viruses such as influenza. Viral proteins engage SRP54 and the translocon, selectively enriching for factors supporting membrane expansion and lipid metabolism while excluding RNA binding and antiviral stress granule proteins. Our findings reveal a sophisticated viral strategy to rewire host protein synthesis pathways and create a replication-favourable subcellular niche, providing insights into viral adaptation.

DOI: https://doi.org/10.1371/journal.ppat.1012766
Methods Mol Biol. 2025 ;2860 273-285

Sample Preparation for Global Metabolic Profiling of Vaccinia Virus-Infected Primary Human Foreskin Fibroblasts.

Anil Pant, Sebastian O Wendel, Nicholas A Wallace, Zhilong Yang.

  Vaccinia virus (VACV), the prototype member of the Poxviridae family, has played a crucial role in medicine as a key component in the development of smallpox vaccines, contributing to the eradication of this deadly disease. Beyond its historical significance, VACV continues to be pivotal in researching metabolic alterations induced by viral infections. Studies have revealed that VACV can impact pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and lipid metabolism in host cells, offering valuable insights into host-virus interactions and broader cellular metabolism. The preference for primary cells, such as human foreskin fibroblasts (HFFs), over cancer cells in metabolic studies is justified for their physiological relevance, representing native cell types with genetic stability. Metabolic profiling is an ideal tool for studying virus-induced metabolic alterations, providing a comprehensive analysis of changes in cellular metabolism triggered by viral infections. This chapter outlines a protocol for extracting HFFs, culturing, infecting them with VACV, and conducting untargeted global metabolic profiling to elucidate detailed metabolic statuses of the infected cells. This protocol may be modified for understanding the intricacies of host-virus interactions at the metabolic interface for other poxviruses and non-poxviruses.

Keywords:  Global metabolic profiling; HFFs; Metabolomics; Poxvirus; Vaccinia virus

DOI:  https://doi.org/10.1007/978-1-0716-4160-6_18
PLoS Pathog. 2024 Dec 02. 20(12): e1012737

Newcastle disease virus infection induces parthanatos in tumor cells via calcium waves.

Yang Qu, Siyuan Wang, Hui Jiang, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Venugopal Nair, Zengqi Yang, Yingjie Sun, Chan Ding.

Parthanatos is distinct from caspase-dependent apoptosis in that it does not necessitate the activation of caspase cascades; Instead, it relies on the translocation of Apoptosis-inducing Factor (AIF) from the mitochondria to the nucleus, resulting in nuclear DNA fragmentation. Newcastle Disease Virus (NDV) is an oncolytic virus that selectively targets and kills tumor cells by inducing cell apoptosis. It has been reported that NDV triggers classic apoptosis through the mitochondrial pathway. In this study, we observed that NDV infection induced endoplasmic reticulum stress (ERS), which caused a rapid release of endogenous calcium ions (Ca2+). This cascade of events resulted in mitochondrial depolarization, loss of mitochondrial membrane potential, and structural remodeling of the mitochondria. The overload of Ca2+ also initiated an increase in mitochondrial membrane permeability, facilitating the transfer of AIF to the nucleus to induce apoptosis. Damaged mitochondria produced excessive reactive oxygen species (ROS), which further exacerbated mitochondrial damage and increased mitochondrial membrane permeability, thus promoting additional intracellular Ca2+ accumulation and ultimately triggering an ROS burst. Collectively, these findings indicate that NDV infection promotes excessive calcium accumulation and ROS generation, leading to mitochondrial damage that releases more calcium and ROS, creating a feedback loop that exacerbates AIF-dependent parthanatos. This study not only provides a novel perspective on the oncolytic mechanism of NDV but also highlights new targets for antiviral research.

DOI: https://doi.org/10.1371/journal.ppat.1012737
J Cell Biochem. 2024 Dec 05. e30683

Intrinsic Factors Behind the Long-COVID: V. Immunometabolic Disorders.

Muhamed Adilović, Altijana Hromić-Jahjefendić, Lejla Mahmutović, Jasmin Šutković, Alberto Rubio-Casillas, Elrashdy M Redwan, Vladimir N Uversky.

  The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID-19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID-19 and its long-term repercussions, which is the focus of this review paper.

Keywords:  cytokine storm; immunometabolism; long COVID; metabolic syndrome; therapeutic approaches

DOI:  https://doi.org/10.1002/jcb.30683
Brain Behav Immun. 2024 Nov 28. pii: S0889-1591(24)00720-7. [Epub ahead of print]

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses.

Xueqi Li, Arvid Edén, Susmita Malwade, Janet L Cunningham, Jonas Bergquist, Jacob Ahlberg Weidenfors, Carl M Sellgren, Göran Engberg, Fredrik Piehl, Magnus Gisslen, Eva Kumlien, Johan Virhammar, Funda Orhan, Elham Rostami, Lilly Schwieler, Sophie Erhardt.

  Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients. Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway. The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients. In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Keywords:  Cognition; Infectious disease; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbi.2024.11.031
Metabolomics. 2024 Dec 04. 21(1): 3

Untargeted metabolomics and lipidomics in COVID-19 patient plasma reveals disease severity biomarkers.

Jinchun Sun, Megan Peters, Li-Rong Yu, Vikrant Vijay, Mallikarjun Bidarimath, Mona Agrawal, Armando S Flores-Torres, Amanda M Green, Keith Burkhart, Jessica Oliphant, Heather S Smallwood, Richard D Beger.

   INTRODUCTION: Coronavirus disease 2019 (COVID-19) has widely varying clinical severity. Currently, no single marker or panel of markers is considered standard of care for prediction of COVID-19 disease progression. The goal of this study is to gain mechanistic insights at the molecular level and to discover predictive biomarkers of severity of infection and outcomes among COVID-19 patients.
METHOD: This cohort study (n = 76) included participants aged 16-78 years who tested positive for SARS-CoV-2 and enrolled in Memphis, TN between August 2020 to July 2022. Clinical outcomes were classified as Non-severe (n = 39) or Severe (n = 37). LC/HRMS-based untargeted metabolomics/lipidomics was conducted to examine the difference in plasma metabolome and lipidome between the two groups.
RESULTS: Metabolomics data indicated that the kynurenine pathway was activated in Severe participants. Significant increases in short chain acylcarnitines, and short and medium chain acylcarnitines containing OH-FA chain in Severe vs. Non-severe group, which indicates that (1) the energy pathway switched to FA β-oxidation to maintain the host energy homeostasis and to provide energy for virus proliferation; (2) ROS status was aggravated in Severe vs. Non-severe group. Based on PLS-DA and correlation analysis to severity score, IL-6, and creatine, a biomarker panel containing glucose (pro-inflammation), ceramide and S1P (inflammation related), 4-hydroxybutyric acid (oxidative stress related), testosterone sulfate (immune related), and creatine (kidney function), was discovered. This novel biomarker panel plus IL-6 with an AUC of 0.945 provides a better indication of COVID-19 clinical outcomes than that of IL-6 alone or the three clinical biomarker panel (IL-6, glucose and creatine) with AUCs of 0.875 or 0.892.

Keywords:  Clinical outcomes; Coronavirus disease 2019 (COVID-19); Metabolomics; Risk factors; Severity plasma biomarkers

DOI:  https://doi.org/10.1007/s11306-024-02195-y
Heliyon. 2024 Nov 30. 10(22): e40297

Reactive oxygen species induced by SARS-CoV-2 infection can induce EMT in solid tumors: Potential role of COVID-19 in chemo-resistance and metastasis.

Melina Moulaeian, Saeid Ferdousmakan, Sara Banihashemi, Shadi Homayounfar, Ajay Prakash Pasupulla, Yalda Malekzadegan.

  The coronavirus disease 2019 (COVID-19) pandemic has raised discussion over the connection between viral infections and the biology of cancer. Research has investigated the relationship between signaling pathways stimulated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may be involved in the progression of cancer, resistance to chemotherapy, and metastasis. However, the exact cellular and molecular mechanisms of the effects of SARS-CoV-2 infection on cancer progression, chemo-resistance, metastasis, and recurrence have not been fully understood. Recently, studies indicate that SARS-CoV-2 might induce inflammatory responses and cytokine storm, which can affect cellular signaling pathways associated with the epithelial-mesenchymal transition (EMT). We address the possible involvement of reactive oxygen species (ROS) induced by SARS-CoV-2 infection in treatment resistance, metastatic recurrence, and the activation of EMT in solid tumors in this review. We emphasize the disturbance of mitochondria dysfunction, the overproduction of ROS in SARS-CoV-2-infected cells, and its consequences for the beginning of EMT. We also suggested possible processes associated with ROS influence on EMT, inflammatory signaling pathways, and viral interaction with mitochondria. Gaining knowledge about ROS's function in SARS CoV-2 condition, promoting EMT will help to develop effective strategies during therapy treatments by lowering drug resistance and metastatic recurrence in cancer patient.

Keywords:  COVID-19; Chemoresistance; Epithelial-mesenchymal transition; Metastatic recurrence; Reactive oxygen species; SARS-CoV-2; Solid tumors

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40297
J Neurovirol. 2024 Dec 03.

High glucose potentiates Zika virus induced-astroglial dysfunctions.

Natalie Katherine Thomaz, Larissa Daniele Bobermin, Patrícia Sesterheim, Ana Paula Muterle Varela, Thais Fumaco, Marina Seady, Belisa Parmeggiani, Marina Concli Leite, Guilhian Leipnitz, Lucélia Santi, Walter O Beys-da-Silva, Jorge Almeida Guimarães, Paulo M Roehe, Carlos-Alberto Gonçalves, Diogo Onofre Souza, André Quincozes-Santos.

Zika virus (ZIKV) is a neurotropic flavivirus that induces congenital Zika syndrome and neurodevelopmental disorders. Given that ZIKV can infect and replicate in neural cells, neurological complications in adult brain are also observed. Glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration. These cells actively participate in metabolic, inflammatory and redox processes, and consequently, in the pathophysiology of neurodegenerative diseases, including diabetic encephalopathy. In this sense, changes in glucose metabolism can support the inflammatory activity of astroglial cells; however, the effects of increased glucose concentration during ZIKV infection have not yet been explored in astroglial cells. Here, we evaluated functional parameters of astroglial cells exposed to ZIKV upon normal and high glucose concentrations, focusing on inflammatory profile, oxidative stress, and expression of critical genes for astroglial functions. High glucose potentiated the pro-inflammatory and oxidative effects of ZIKV, as well as potentiated the downregulation of signaling pathways, such as Nrf-2 (nuclear factor erythroid derived 2 like 2), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and poly (ADP-ribose) polymerase (PARP). In summary, our results suggest that high glucose can favor the activation of inflammatory signaling while impairing cytoprotective pathways in astroglial cells exposed to ZIKV and reinforce the hypothesis that this virus is highly neurotrophic, with significant impact in glial cells.

DOI: https://doi.org/10.1007/s13365-024-01238-3
Phytomedicine. 2024 Nov 30. pii: S0944-7113(24)00935-8. [Epub ahead of print]136 156279

Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC).

Jarinya Chaopreecha, Nut Phueakphud, Ampa Suksatu, Sucheewin Krobthong, Suwimon Manopwisedjaroen, Nattawadee Panyain, Suradej Hongeng, Arunee Thitithanyanont, Patompon Wongtrakoongate.

   BACKGROUND: Andrographolide is a medicinal compound which possesses anti-SARS-CoV-2 activity. A number of cellular targets of andrographolide have been identified by target predictions and computational studies.
PURPOSE: However, a potential cellular target of andrographolide has never been explored in SARS-CoV-2 infected lung epithelial cells. We aimed to identify cellular pathways involved in andrographolide-mediated anti-SARS-CoV-2 activity.
METHODS: The viral infection was determined by immunofluorescence staining, enzyme-linked immunosorbent assay and focus-forming assay. Proteomic analysis was employed to identify cellular pathways and key proteins controlled by andrographolide in the human lung epithelial cells Calu-3 infected by SARS-CoV-2. Immunofluorescence staining was used to test protein expression and localization. Western blot and realtime PCR were utilized to elucidate gene expression. Cellular glutathione level was examined by a reduced/oxidized glutathione assay. An ectopic gene expression was delivered by plasmid transfection.
RESULTS: Gene ontology analysis indicates that proteins involved in nuclear factor erythroid 2-related factor 2 (NRF2)-regulated pathways were differentially expressed by andrographolide. Notably, andrographolide increased expression and nuclear localization of the transcription factor NRF2. In addition, transcriptional expression of GCLC and glutamate-cysteine ligase modifier subunit (GCLM), which are NRF2 target genes, were induced by andrographolide. We further find that infection of SARS-CoV-2 resulted in a reduction of glutathione level in Calu-3; the effect that was rescued by andrographolide. Moreover, andrographolide also induced expression of the glutathione producing enzyme GCLC in SARS-CoV-2 infected lung epithelial cells. Importantly, an ectopic over-expression of GCLC or treatment of N-acetyl-L-cysteine in Calu-3 cells led to a decrease in SARS-CoV-2 infection.
CONCLUSION: Collectively, our findings suggest the interplay between GCLC-mediated glutathione biogenesis induced by andrographolide and the anti-SARS-CoV-2 activity. The glutathione biogenesis and recycling pathways should be further exploited as a targeted therapy against SARS-CoV-2 infection.

Keywords:  Andrographolide; GCLC; Glutathione; Proteomic; SAR-CoV-2

DOI:  https://doi.org/10.1016/j.phymed.2024.156279
Int J Med Sci. 2024 ;21(15): 3034-3045

Oxidative stress indexes as biomarkers of the severity in COVID-19 patients.

Xin Liu, Ruohong Chen, Binghui Li, Jialiang Zhang, Peiting Liu, Bingchu Li, Fengfan Li, Weilin Zhang, Xing Lyu, Min Hu.

  Background: SARS-CoV-2 causes a global pandemic, with severe and critically ill COVID-19 patients often experiencing poor prognoses. Severe infection with SARS-CoV-2 is associated with oxidative stress (OS) and inflammation. Detecting markers of macromolecular damage caused by OS may provide valuable insights into disease progression. Methods: This study included 187 patients with laboratory-confirmed SARS-CoV-2 infection, categorized into non-severe, severe, and critically ill COVID-19 groups. We monitored the changes in serum indexes such as oxidized low-density lipoprotein (OxLDL), OxLDL/LDL-C ratio, advanced oxidation protein products (AOPP), 3-nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHdG), lipoprotein-associated phospholipase A2 (Lp-PLA2) and thromboxane B2 (TXB2) in patients with different clinical types. Results: 48 non-severe patients, 90 severe patients, and 49 critically ill patients were enrolled. Compared with the non-severe group, OxLDL level and OxLDL/LDL-C ratio were increased in severe COVID-19 patients and critically ill COVID-19 patients, while 3-NT and TXB2 concentrations were lower in critically ill COVID-19 patients. Critically ill COVID-19 patients also exhibited lower concentrations of Lp-PLA2 and a higher OxLDL/LDL-C ratio compared to severe COVID-19 patients. No significant differences were observed in AOPP and 8-OHdG concentrations. Spearman's correlation analysis revealed that CRP was associated with OxLDL, OxLDL/LDL-C ratio, AOPP, 3-NT, TXB2, and Lp-PLA2 (P <0.05). OxLDL was identified as an independent risk factor for progression from non-severe to severe/critically ill COVID-19. OxLDL and OxLDL/LDL-C ratio demonstrated good discriminatory value between non-severe and severe/critically ill COVID-19, with the OxLDL/LDL-C ratio also distinguishing between severe and critically ill patients. Conclusion: Patients with severe and critically ill COVID-19 exhibit elevated levels of oxidative damage to lipoproteins. OxLDL and the OxLDL/LDL-C ratio can serve as biomarkers for assessing disease severity in COVID-19 patients.

Keywords:  3-nitrotyrosine; COVID-19; oxidative stress; oxidized low-density lipoprotein

DOI:  https://doi.org/10.7150/ijms.102879