bims-mevinf 2024-12-01 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–12–01
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Dynamic metabolic modeling of ATP allocation during viral infection.
The interplay of EBV virus and cell metabolism in lung cancer.
Longitudinal 1H NMR-Based Metabolomics in Saliva Unveils Signatures of Transition from Acute to Post-Acute Phase of SARS-CoV-2 Infection.
Manipulation of Host Cholesterol by SARS-CoV-2.
The Effects of Different Respiratory Viruses on the Oxidative Stress Marker Levels in an In Vitro Model: A Pilot Study.
Comprehensive transcriptomic analysis identifies cholesterol transport pathway as a therapeutic target of porcine epidemic diarrhea coronavirus.
Metabolomic Insights into COVID-19 Severity: A Scoping Review.
Analysis of the Urine Volatilome of COVID-19 Patients and the Possible Metabolic Alterations Produced by the Disease.
Hepatitis B small surface protein hijacking Bip is initial and essential to promote lipid synthesis.

bioRxiv. 2024 Nov 13. pii: 2024.11.12.623198. [Epub ahead of print]

Dynamic metabolic modeling of ATP allocation during viral infection.

Alvin Lu, Ilija Dukovski, Daniel Segrè.

Viral pathogens, like SARS-CoV-2, hijack the host's macromolecular production machinery, imposing an energetic burden that is distributed across cellular metabolism. To explore the dynamic metabolic tension between the host's survival and viral replication, we developed a computational framework that uses genome-scale models to perform dynamic Flux Balance Analysis of human cell metabolism during virus infections. Relative to previous models, our framework addresses the physiology of viral infections of non-proliferating host cells through two new features. First, by incorporating the lipid content of SARS-CoV-2 biomass, we discovered activation of previously overlooked pathways giving rise to new predictions of possible drug targets. Furthermore, we introduce a dynamic model that simulates the partitioning of resources between the virus and the host cell, capturing the extent to which the competition depletes the human cells from essential ATP. By incorporating viral dynamics into our COMETS framework for spatio-temporal modeling of metabolism, we provide a mechanistic, dynamic and generalizable starting point for bridging systems biology modeling with viral pathogenesis. This framework could be extended to broadly incorporate phage dynamics in microbial systems and ecosystems.

DOI: https://doi.org/10.1101/2024.11.12.623198
J Cell Mol Med. 2024 Nov;28(22): e70088

The interplay of EBV virus and cell metabolism in lung cancer.

Hongwei Wang.

  Epstein-Barr virus infection has been implicated in various cancers, including lung cancer, where it influences cellular metabolism to promote tumorigenesis. This review examines the complex interplay between Epstein-Barr virus and cell metabolism in lung cancer, highlighting viral mechanisms of metabolic reprogramming and their implications for therapeutic strategies. Key viral proteins such as LMP1 and LMP2A manipulate glycolysis, glutaminolysis and lipid metabolism to support viral replication and immune evasion within the tumour microenvironment. Understanding these interactions provides insights into novel therapeutic approaches targeting viral-induced metabolic vulnerabilities in Epstein-Barr virus-associated lung cancer.

Keywords:  Epstein–Barr virus; cell metabolism; glycolysis; immune evasion; lung cancer

DOI:  https://doi.org/10.1111/jcmm.70088
Viruses. 2024 Nov 13. pii: 1769. [Epub ahead of print]16(11):

Longitudinal 1H NMR-Based Metabolomics in Saliva Unveils Signatures of Transition from Acute to Post-Acute Phase of SARS-CoV-2 Infection.

Luiza Tomé Mendes, Marcos C Gama-Almeida, Desirée Lopes Reis, Ana Carolina Pires E Silva, Rômulo Leão Silva Neris, Rafael Mello Galliez, Terezinha Marta Pereira Pinto Castiñeiras, On Behalf Of The Ufrj Covid-Working Group, Christian Ludwig, Ana Paula Valente, Gilson Costa Dos Santos Junior, Tatiana El-Bacha, Iranaia Assunção-Miranda.

  COVID-19 can range from a mild to severe acute respiratory syndrome and also could result in multisystemic damage. Additionally, many people develop post-acute symptoms associated with immune and metabolic disturbances in response to viral infection, requiring longitudinal and multisystem studies to understand the complexity of COVID-19 pathophysiology. Here, we conducted a 1H Nuclear Magnetic Resonance metabolomics in saliva of symptomatic subjects presenting mild and moderate respiratory symptoms to investigate prospective changes in the metabolism induced after acute-phase SARS-CoV-2 infection. Saliva from 119 donors presenting non-COVID and COVID-19 respiratory symptoms were evaluated in the acute phase (T1) and the post-acute phase (T2). We found two clusters of metabolite fluctuation in the COVID-19 group. Cluster 1, metabolites such as glucose, (CH3)3 choline-related metabolites, 2-hydroxybutyrate, BCAA, and taurine increased in T2 relative to T1, and in cluster 2, acetate, creatine/creatinine, phenylalanine, histidine, and lysine decreased in T2 relative to T1. Metabolic fluctuations in the COVID-19 group were associated with overweight/obesity, vaccination status, higher viral load, and viral clearance of the respiratory tract. Our data unveil metabolic signatures associated with the transition to the post-acute phase of SARS-CoV-2 infection that may reflect tissue damage, inflammatory process, and activation of tissue repair cascade. Thus, they contribute to describing alterations in host metabolism that may be associated with prolonged symptoms of COVID-19.

Keywords:  SARS-CoV-2 infection; long COVID; metabolic fluctuation; metabolome; saliva

DOI:  https://doi.org/10.3390/v16111769
bioRxiv. 2024 Nov 14. pii: 2024.11.13.623299. [Epub ahead of print]

Manipulation of Host Cholesterol by SARS-CoV-2.

Aliza Doyle, Baley A Goodson, Oralia M Kolaczkowski, Rui Liu, Jingyue Jia, Hu Wang, Xianlin Han, Chunyan Ye, Steven B Bradfute, Alison M Kell, Monica Rosas Lemus, Jing Pu.

SARS-CoV-2 infection is associated with alterations in host lipid metabolism, including disruptions in cholesterol homeostasis. However, the specific mechanisms by which viral proteins influence cholesterol remain incompletely understood. Here, we report that SARS-CoV-2 infection induces cholesterol sequestration within lysosomes, with the viral protein ORF3a identified as the primary driver of this effect. Mechanistically, we found that ORF3a interacts directly with the HOPS complex subunit VPS39 through a hydrophobic interface formed by residues W193 and Y184. A W193A mutation in ORF3a significantly rescues cholesterol egress and corrects the mislocalization of the lysosomal cholesterol transporter NPC2, which is caused by defective trafficking of the trans-Golgi network (TGN) sorting receptor, the cation-independent mannose-6-phosphate receptor (CI-MPR). We further observed a marked reduction in bis(monoacylglycero)phosphate (BMP), a lipid essential for lysosomal cholesterol egress, in both SARS-CoV-2-infected cells and ORF3a-expressing cells, suggesting BMP reduction as an additional mechanism of SARS-CoV-2-caused cholesterol sequestration. Inhibition of lysosomal cholesterol egress using the compound U18666A significantly decreased SARS-CoV-2 infection, highlighting a potential viral strategy of manipulating lysosomal cholesterol to modulate host cell susceptibility. Our findings reveal that SARS-CoV-2 ORF3a disrupts cellular cholesterol transport by altering lysosomal protein trafficking and BMP levels, providing new insights into virus-host interactions that contribute to lipid dysregulation in infected cells.

DOI: https://doi.org/10.1101/2024.11.13.623299
Int J Mol Sci. 2024 Nov 11. pii: 12088. [Epub ahead of print]25(22):

The Effects of Different Respiratory Viruses on the Oxidative Stress Marker Levels in an In Vitro Model: A Pilot Study.

Barbara Bażanów, Katarzyna Michalczyk, Alina Kafel, Elżbieta Chełmecka, Bronisława Skrzep-Poloczek, Aleksandra Chwirot, Kamil Nikiel, Aleksander Olejnik, Alicja Suchocka, Michał Kukla, Bartosz Bogielski, Jerzy Jochem, Dominika Stygar.

  Respiratory viruses are among the most common causes of human infections. Examining pathological processes linked to respiratory viral infections is essential for diagnosis, treatment strategies, and developing novel therapeutics. Alterations in oxidative stress levels and homeostasis are significant processes associated with respiratory viral infections. The study aimed to compare selected oxidative stress markers: total oxidative status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI) levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities in normal (MRC5 cell line) and tumor (A549 cell line) lung cells infected with human coronaviruses (HCoV) OC43 and 229E, human adenovirus type 5 (HAdV5), or human rhinovirus A (HRV A). We observed that a respiratory viral infection more significantly affected non-enzymatic oxidative stress markers in a lung adenocarcinoma model (A549 cells), while human lung fibroblasts (MRC-5 cell line) presented changes in enzymatic and non-enzymatic oxidative stress markers. We suggest that further detailed research is required to analyze this phenomenon.

Keywords:  human adenovirus; human coronavirus; human rhinovirus; in vitro model; lung carcinoma A549 cells; lung fibroblast MRC-5 cells; oxidative stress markers; respiratory virus

DOI:  https://doi.org/10.3390/ijms252212088
Virus Res. 2024 Nov 23. pii: S0168-1702(24)00195-3. [Epub ahead of print]350 199502

Comprehensive transcriptomic analysis identifies cholesterol transport pathway as a therapeutic target of porcine epidemic diarrhea coronavirus.

Lilei Lv, Huaye Luo, Min Zhang, Chuntao Wu, Yifeng Jiang, Wu Tong, Guoxin Li, Yanjun Zhou, Yanhua Li, Zhao Wang, Changlong Liu.

  Porcine epidemic diarrhea virus (PEDV) is a highly contagious virus that poses a serious threat to the global pig industry. Despite extensive efforts, the mechanism underlying virus entry for PEDV remains elusive. In this study, we first identified PEDV-susceptible and non-susceptible cell lines by using PEDV spike pseudotyped vesicular stomatitis virus. Subsequently, we conducted a comprehensive transcriptomic analysis on these cell lines. Through integrating differential expression gene analysis with weighted gene co-expression network analysis, we identified the key pathways that are correlated with the PEDV entry. Our analysis revealed a strong correlation between cholesterol, sterols, and lipid transport with PEDV entry, suggesting a potential role for cholesterol transport in the PEDV entry. For further investigation, we treated Huh7, Vero and LLC-PK1 cells with a cholesterol transport inhibitor, ezetimibe, and observed a significant inhibition of PEDV entry and subsequent viral replication in these cells. Interestingly, pre-treating Huh7 cells with ezetimibe resulted in an increase in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses. Moreover, we found that cholesterol could facilitate the entry of PEDV into Huh7 and Vero cells, and this promoting effect can be blocked by ezetimibe. These findings suggest that targeting cholesterol transport specifically inhibits PEDV entry into susceptible cells. Our study offers novel insights into the mechanism of PEDV entry and the development of new therapeutic strategies against this economically important virus.

Keywords:  Cholesterol transport; Coronavirus; Ezetimibe; PEDV; Viral entry

DOI:  https://doi.org/10.1016/j.virusres.2024.199502
Metabolites. 2024 Nov 12. pii: 617. [Epub ahead of print]14(11):

Metabolomic Insights into COVID-19 Severity: A Scoping Review.

Eric Pimentel, Mohammad Mehdi Banoei, Jasnoor Kaur, Chel Hee Lee, Brent W Winston.

   BACKGROUND: In 2019, SARS-CoV-2, the novel coronavirus, entered the world scene, presenting a global health crisis with a broad spectrum of clinical manifestations. Recognizing the significance of metabolomics as the omics closest to symptomatology, it has become a useful tool for predicting clinical outcomes. Several metabolomic studies have indicated variations in the metabolome corresponding to different disease severities, highlighting the potential of metabolomics to unravel crucial insights into the pathophysiology of SARS-CoV-2 infection.
METHODS: The PRISMA guidelines were followed for this scoping review. Three major scientific databases were searched: PubMed, the Directory of Open Access Journals (DOAJ), and BioMed Central, from 2020 to 2024. Initially, 2938 articles were identified and vetted with specific inclusion and exclusion criteria. Of these, 42 articles were retrieved for analysis and summary.
RESULTS: Metabolites were identified that were repeatedly noted to change with COVID-19 and its severity. Phenylalanine, glucose, and glutamic acid increased with severity, while tryptophan, proline, and glutamine decreased, highlighting their association with COVID-19 severity. Additionally, pathway analysis revealed that phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis were the most significantly impacted pathways in COVID-19 severity.
CONCLUSIONS: COVID-19 severity is intricately linked to significant metabolic alterations that span amino acid metabolism, energy production, immune response modulation, and redox balance.

Keywords:  COVID-19; SARS-CoV-2; acute respiratory distress syndrome (ARDS); disease severity; metabolomics; scoping review

DOI:  https://doi.org/10.3390/metabo14110617
Metabolites. 2024 Nov 19. pii: 638. [Epub ahead of print]14(11):

Analysis of the Urine Volatilome of COVID-19 Patients and the Possible Metabolic Alterations Produced by the Disease.

Jennifer Narro-Serrano, Maruan Shalabi-Benavent, José María Álamo-Marzo, Álvaro Maximiliam Seijo-García, Frutos Carlos Marhuenda-Egea.

  Alterations in metabolism caused by SARS-CoV-2 infection have been highlighted in various investigations and have been used to search for biomarkers in different biological matrices. However, the selected biomarkers vary greatly across studies. Our objective is to provide a robust selection of biomarkers, including results from different sample treatments in the analysis of volatile organic compounds (VOCs) present in urine samples from patients with COVID-19. Between September 2021 and May 2022, urine samples were collected from 35 hospitalized COVID-19 patients and 32 healthy controls. The samples were analyzed by headspace (HS) solid phase microextraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). Analyses were conducted on untreated urine samples and on samples that underwent specific pretreatments: lyophilization and treatment with sulfuric acid. Partial Least Squares Linear Discriminant Analysis (PLS-LDA) and Subwindow Permutation Analysis (SPA) models were established to distinguish patterns between COVID-19 patients and healthy controls. The results identify compounds that are present in different proportions in urine samples from COVID-19 patients compared to those from healthy individuals. Analysis of urine samples using HS-SPME-GC-MS reveals differences between COVID-19 patients and healthy individuals. These differences are more pronounced when methods that enhance VOC formation are used. However, these pretreatments can cause reactions between sample components, creating additional products or removing compounds, so biomarker selection could be altered. Therefore, using a combination of methods may be more informative when evaluating metabolic alterations caused by viral infections and would allow for a better selection of biomarkers.

Keywords:  COVID-19; GC-MS; SARS-CoV-2; VOCs; biomarkers; metabolomics; urine volatilome

DOI:  https://doi.org/10.3390/metabo14110638
J Proteomics. 2024 Nov 21. pii: S1874-3919(24)00290-2. [Epub ahead of print] 105358

Hepatitis B small surface protein hijacking Bip is initial and essential to promote lipid synthesis.

Tao Zuo, Sha Jing, Peiru Chen, Tao Zhang, Yihao Wang, Yanchang Li, Lei Chang, Xingyu Rong, Na Li, Zhenwen Zhao, Chao Zhao, Ping Xu.

  To date, the molecular pathogenic mechanisms between HBsAg and liver metabolic disorders have not been fully understood. To explore the overall effects of HBsAg on liver tissues from HBV transgenic mice, proteome, interactome, and signal pathway analysis were employed to uncover the underlying mechanisms. Bioinformatics analysis of 191 differentially expressed proteins suggested that HBV upregulated the expression of multiple enzymes involved in lipid synthesis, and small HBs (SHBs) caused lipid accumulation in cells. Further studies showed that SHBs bound to binding immunoglobulin protein (Bip), which normally functions in cell homeostasis against the unfolded protein response (UPR) signaling via occupying inositol-requiring enzyme 1 (IRE1). Hijacking Bip by SHBs alleviated the inhibition of post-endoplasmic reticulum (ER) signaling and sequential activation of the IRE1 downstream transcription factors involved in lipid synthesis, such as spliced X-box binding protein 1 (sXBP1) and sterol regulatory element-binding protein 1 (SREBP1), leading to lipid metabolism disorder. The restoration of Bip can alleviate ER stress, and block the sequential post-ER signaling caused by SHBs. This study revealed a new pathway through which SHBs promote lipid disorder, and suggests that Bip may serve as a novel target for intervention in HBV related liver diseases. SIGNIFICANCE: In this study, we found a new pathway promoting the lipid disorder by SHBs through quantitative proteomics studies, and Bip may serve as a novel target for intervention in HBV related liver diseases. These findings highlight a novel role of SHBs in regulating cell lipid metabolism and provide an insight into the relationship between HBV infection and liver fatty disorders, which may serve as a potential therapeutic target for intervention of HBV related liver diseases.

Keywords:  Bip; ER stress; HBs; Hepatic steatosis; Lipid disorder; SILAM

DOI:  https://doi.org/10.1016/j.jprot.2024.105358