bims-mevinf 2024-09-29 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–09–29
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Stearoyl coenzyme A desaturase 1 (SCD1) regulates foot-and-mouth disease virus replication by modulating host cell lipid metabolism and viral protein 2C-mediated replication complex formation.
Porcine epidemic diarrhea virus E protein induces unfolded protein response through activating both PERK and ATF6 rather than IRE1 signaling pathway.
The unique metabolic and lipid profiles of patients with severe COVID-19 compared to severe community-acquired pneumonia: a potential prognostic and therapeutic target.
Orally Bioavailable RORγ/DHODH Dual Host-Targeting Small Molecules with Broad-Spectrum Antiviral Activity.
Metabolomic profiling of dengue infection: unraveling molecular signatures by LC-MS/MS and machine learning models.
Let-7f-5p Modulates Lipid Metabolism by Targeting Sterol Regulatory Element-Binding Protein 2 in Response to PRRSV Infection.
Exploring metabolic anomalies in COVID-19 and post-COVID-19: a machine learning approach with explainable artificial intelligence.
Persistent Post COVID-19 Endothelial Dysfunction and Oxidative Stress in Women.
Duck hepatitis A virus 1-encoded 2B protein disturbs ion and organelle homeostasis to promote NF-κB/NLRP3-mediated inflammatory response.
Transition metals and oxidation reactions trigger stargate opening during the initial stages of the replicative cycle of the giant Tupanvirus.

J Virol. 2024 Sep 26. e0090224

Stearoyl coenzyme A desaturase 1 (SCD1) regulates foot-and-mouth disease virus replication by modulating host cell lipid metabolism and viral protein 2C-mediated replication complex formation.

Bonan Lv, Yuncong Yuan, Zhuang Yang, Xingran Wang, Jianjun Hu, Yidan Sun, Hang Du, Xuemei Liu, Huimin Duan, Ruyi Ding, Zishu Pan, Xiao-Feng Tang, Chao Shen.

  The life cycle of foot-and-mouth disease virus (FMDV) is tightly regulated by host cell lipid metabolism. In previous studies, we reported downregulated expression of stearoyl coenzyme A desaturase-1 (SCD1), a key enzyme of fatty acid metabolism, in BHK-VEC cells (a virus-negative cell line derived from BKH-21 cells with persistent FMDV infection) on comparing transcriptomic data for BHK-VEC and BHK-21 cells (Y. Yuan et al., Front Cell Infect Microbiol 12:940906, 2022, https://doi.org/10.3389/fcimb.2022.940906; L. Han et al., Vet Microbiol 263:109247, 2021, https://doi.org/10.1016/j.vetmic.2021.109247). In the present study, we identify that SCD1 regulates FMDV replication. SCD1 overexpression or exogenous addition of oleic acid (OA), a product of the enzymatic activity of SCD1, increased FMDV replication in both BHK-21 cells and SCD1-knockdown cells. Overexpression of SCD1 or exogenous addition of OA restored FMDV infection and replication in BHK-VEC cells, and OA also promoted FMDV replication in BHK-21 cells with persistent FMDV infection. SCD1 recruited the nonstructural FMDV protein 2C to a detergent-resistant membrane located in the perinuclear region of cells to form replication complexes. Inhibiting SCD1 enzyme activity resulted in a significantly decreased number of FMDV replication complexes with abnormal morphology. Inhibition of SCD1 activity also effectively decreased the replication of other RNA viruses such as respiratory enteric orphan virus-3-176, poliovirus-1, enterovirus 71, and vesicular stomatitis virus. Our results demonstrate that SCD1, as a key host regulator of RNA virus replication, is a potential target for developing novel drugs against infections by RNA viruses.
IMPORTANCE: Many positive-stranded RNA viruses, including foot-and-mouth disease virus (FMDV), alter host membranes and lipid metabolism to create a suitable microenvironment for their survival and replication within host cells. In FMDV-infected cells, the endoplasmic reticulum membrane is remodeled, forming vesicular structures that rely heavily on increased free fatty acids, thereby linking lipid metabolism to the FMDV replication complex. Nonstructural FMDV protein 2C is crucial for this complex, while host cell enzyme stearoyl coenzyme A desaturase 1 (SCD1) is vital for lipid metabolism. We found that FMDV infection alters SCD1 expression in host cells. Inhibiting SCD1 expression or its enzymatic activity markedly decreases FMDV replication, while supplementing oleic acid, a catalytic product of SCD1, regulates FMDV replication. Additionally, SCD1 forms part of the FMDV replication complex and helps recruit 2C to a detergent-resistant membrane. Our study provides insights into the pathogenesis of FMDV and a potential novel drug target against the virus.

Keywords:  SCD1; foot-and-mouth disease virus; host lipid metabolism; oleic acid; replication complex

DOI:  https://doi.org/10.1128/jvi.00902-24
Virus Genes. 2024 Sep 23.

Porcine epidemic diarrhea virus E protein induces unfolded protein response through activating both PERK and ATF6 rather than IRE1 signaling pathway.

Liang Zheng, Ying Yang, Mingxin Ma, Qin Hu, Zhijun Wu, Matthew Kay, Xiaoge Yang, Liwei Yin, Fusheng Ding, Hua Zhang.

  Porcine epidemic diarrhea virus (PEDV) small envelope protein (E) plays important roles in virus budding, assembly, and release. Our previous study found that PEDV E protein localizes in the endoplasmic reticulum (ER) to trigger the unfolded protein response (UPR). However, how UPR is directly regulated by PEDV E protein remains elusive. Thus, in this study, we investigated the expression of ER chaperone glucose-regulated protein 78 (GRP78) and activations of the three main UPR signaling pathways to elucidate the underlying mechanisms of UPR triggered by PEDV E protein. The results showed that over-expression of PEDV E protein increased expression of GRP78 and induced stronger phosphorylation of both protein kinase RNA-like ER kinase (PERK) and eukaryotic initiation factor-2α (eIF2α), as well as caused the significant degradation of activating transcription factor 6 (ATF6), in both dose- and time-dependent manners. However, PEDV E protein did not induce UPR through the inositol-requiring enzyme 1 (IRE1) signaling pathway, as revealed by the splicing of XBP1 remaining unaffected and unchanged when PEDV E protein was overexpressed. Taken together, these results demonstrate that PEDV E protein induces UPR through activation of both PERK and ATF6 pathways rather than IRE1 signaling. This study not only provides mechanistic details of UPR induced by the PEDV E protein, but also provides insights into these new biologic functions to help us better understand the interactions between PEDV and host cells.

Keywords:  ATF6; E protein; IRE1; PERK; Porcine epidemic diarrhea virus; Unfolded protein response

DOI:  https://doi.org/10.1007/s11262-024-02108-0
Expert Rev Respir Med. 2024 Sep 26.

The unique metabolic and lipid profiles of patients with severe COVID-19 compared to severe community-acquired pneumonia: a potential prognostic and therapeutic target.

Elsa D Ibáñez-Prada, Jose L Guerrero, Ingrid G Bustos, Lizeth León, Yuli V Fuentes, Mary Santamaría-Torres, Juan M Restrepo-Martínez, Cristian C Serrano-Mayorga, Lina Mendez, Salome Gomez-Duque, Carlos A Santacruz, Andrew Conway-Morris, Ignacio Martín-Loeches, Norberto Gonzalez-Juarbe, Mónica P Cala, Luis Felipe Reyes.

   BACKGROUND: Compare the changes and differences in metabolome and lipidome profiles among severe COVID-19 and CAP patients with ARF to identify biomarkers that could be used for personalized diagnosis, prognosis, and treatment.
RESEARCH DESIGN AND METHODS: Plasma samples were taken at hospital admission (baseline) and on the 5th day of hospitalization (follow-up) and examined by RP-LC-QTOF-MS and HILIC-LC-QTOF-MS.
RESULTS: 127 patients, 17 with CAP and 110 with COVID-19, were included. The analysis revealed 87 altered metabolites, suggesting changes in the metabolism of arachidonic acid, glycerolipids, glycerophospholipids, linoleic acid, pyruvate, glycolysis, among others. Most of these metabolites are involved in inflammatory, hypoxic, and thrombotic processes. At baseline, the greatest differences were found in phosphatidylcholine (PC) 31:4 (p < 0.001), phosphoserine (PS) 34:3 (p < 0.001), and phosphatidylcholine (PC) 36:5 (p < 0.001), all of which were notably decreased in COVID-19 patients. At follow-up, the most dysregulated metabolites were monomethyl-phosphatidylethanolamine (PE-Nme) 40:5 (p < 0.001) and phosphatidylcholine (PC) 38:4 (p < 0.001).
CONCLUSIONS: Metabolic and lipidic alterations suggest inhibition of innate anti-inflammatory and anti-thrombotic mechanisms in COVID-19 patients, which might lead to increased viral proliferation, uncontrolled inflammation, and thrombi formation. Results provide novel targets for predictive biomarkers against CAP and COVID-19.
TRIAL REGISTRATION: Not applicable.

Keywords:  COVID-19; Community-acquired pneumonia; Metabolomic; intensive care; lipid profile

DOI:  https://doi.org/10.1080/17476348.2024.2409264
Antiviral Res. 2024 Sep 19. pii: S0166-3542(24)00217-1. [Epub ahead of print] 106008

Orally Bioavailable RORγ/DHODH Dual Host-Targeting Small Molecules with Broad-Spectrum Antiviral Activity.

Alexandra Herrmann, Christian Gege, Christina Wangen, Sabrina Wagner, Melanie Kögler, Arne Cordsmeier, Pascal Irrgang, Wing-Hang Ip, Tatjana Weil, Victoria Hunszinger, Rüdiger Groß, Natalie Heinen, Stephanie Pfaender, Sebastian Reuter, Robert Klopfleisch, Nadja Uhlig, Valentina Eberlein, Leila Issmail, Thomas Grunwald, Benjamin Hietel, Holger Cynis, Jan Münch, Konstantin M J Sparrer, Armin Ensser, Matthias Tenbusch, Thomas Dobner, Daniel Vitt, Hella Kohlhof, Friedrich Hahn.

  Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication. Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively. Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development.

Keywords:  DHODH inhibitor; RORγ inhibitor; broad-spectrum antiviral; dual-targeting small molecules; host-targeting antiviral; human viruses

DOI:  https://doi.org/10.1016/j.antiviral.2024.106008
Metabolomics. 2024 Sep 21. 20(5): 104

Metabolomic profiling of dengue infection: unraveling molecular signatures by LC-MS/MS and machine learning models.

Jhansi Venkata Nagamani Josyula, Aashika Raagavi JeanPierre, Sachin B Jorvekar, Deepthi Adla, Vignesh Mariappan, Sai Sharanya Pulimamidi, Siva Ranganathan Green, Agieshkumar Balakrishna Pillai, Roshan M Borkar, Srinivasa Rao Mutheneni.

   BACKGROUND & OBJECTIVE: The progression of dengue fever to severe dengue (SD) is a major public health concern that impairs the capacity of the medical system to predict and treat dengue patients. Hence, the present study used a metabolomic approach integrated with machine models to identify differentially expressed metabolites in patients with SD compared to nonsevere patients and healthy controls.
METHODS: Comprehensively, the plasma was collected at different clinical phases during dengue without warning signs (DWOW, N = 10), dengue with warning signs (DWW, N = 10), and SD (N = 10) at different stages [i.e., day of admission (DOA), day of defervescence (DOD), and day of convalescent (DOC)] in comparison to healthy control (HC). The samples were subjected to LC‒ESI‒MS/MS to identify metabolites. Statistical and machine learning analyses were performed using R and Python language. Further, biomarker, pathway and correlation analysis was performed to identify potential predictors of dengue.
RESULTS & CONCLUSION: A total of 423 metabolites were identified in all the study groups. Paired and unpaired t-tests revealed 14 highly differentially expressed metabolites between and across the dengue groups, with four metabolites (shikimic acid, ureidosuccinic acid, propionyl carnitine, and alpha-tocopherol) showing significant differences compared to HC. Furthermore, biomarker (ROC) analysis revealed 11 potential molecules with a significant AUC value of 1 that could serve as potential biomarkers for identifying different dengue clinical stages that are beneficial for predicting dengue disease outcomes. The logistic regression model revealed that S-adenosylhomocysteine, hypotaurine, and shikimic acid metabolites could be beneficial indicators for predicting severe dengue, with an accuracy and AUC of 0.75. The data showed that dengue infection is related to lipid metabolism, oxidative stress, inflammation, metabolomic adaptation, and virus manipulation. Moreover, the biomarkers had a significant correlation with biochemical parameters like platelet count, and hematocrit. These results shed some light on host-derived small-molecule biomarkers that are associated with dengue severity and novel insights into metabolomics mechanisms interlinked with disease severity.

Keywords:  Biomarkers; Dengue; LC‒ESI‒MS/MS; Machine learning; Metabolomics

DOI:  https://doi.org/10.1007/s11306-024-02169-0
Vet Sci. 2024 Aug 26. pii: 392. [Epub ahead of print]11(9):

Let-7f-5p Modulates Lipid Metabolism by Targeting Sterol Regulatory Element-Binding Protein 2 in Response to PRRSV Infection.

Dongfeng Jiang, Liyu Yang, Xiangge Meng, Qiuliang Xu, Xiang Zhou, Bang Liu.

  Porcine reproductive and respiratory syndrome (PRRS) has caused substantial damage to the pig industry. MicroRNAs (miRNAs) were found to play crucial roles in modulating the pathogenesis of PRRS virus (PRRSV). In the present study, we revealed that PRRSV induced let-7f-5p to influence lipid metabolism to regulate PRRSV pathogenesis. A transcriptome analysis of PRRSV-infected PK15CD163 cells transfected with let-7f-5p mimics or negative control (NC) generated 1718 differentially expressed genes, which were primarily associated with lipid metabolism processes. Furthermore, the master regulator of lipogenesis SREBP2 was found to be directly targeted by let-7f-5p using a dual-luciferase reporter system and Western blotting. The findings demonstrate that let-7f-5p modulates lipogenesis by targeting SREBP2, providing novel insights into miRNA-mediated PRRSV pathogenesis and offering a potential antiviral therapeutic target.

Keywords:  PRRSV; RNA-seq; SREBP2; let-7f-5p; lipogenesis

DOI:  https://doi.org/10.3390/vetsci11090392
Front Mol Biosci. 2024 ;11 1429281

Exploring metabolic anomalies in COVID-19 and post-COVID-19: a machine learning approach with explainable artificial intelligence.

Juan José Oropeza-Valdez, Cristian Padron-Manrique, Aarón Vázquez-Jiménez, Xavier Soberon, Osbaldo Resendis-Antonio.

  The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant challenges worldwide, including diverse clinical outcomes and prolonged post-recovery symptoms known as Long COVID or Post-COVID-19 syndrome. Emerging evidence suggests a crucial role of metabolic reprogramming in the infection's long-term consequences. This study employs a novel approach utilizing machine learning (ML) and explainable artificial intelligence (XAI) to analyze metabolic alterations in COVID-19 and Post-COVID-19 patients. Samples were taken from a cohort of 142 COVID-19, 48 Post-COVID-19, and 38 control patients, comprising 111 identified metabolites. Traditional analysis methods, like PCA and PLS-DA, were compared with ML techniques, particularly eXtreme Gradient Boosting (XGBoost) enhanced by SHAP (SHapley Additive exPlanations) values for explainability. XGBoost, combined with SHAP, outperformed traditional methods, demonstrating superior predictive performance and providing new insights into the metabolic basis of the disease's progression and aftermath. The analysis revealed metabolomic subgroups within the COVID-19 and Post-COVID-19 conditions, suggesting heterogeneous metabolic responses to the infection and its long-term impacts. Key metabolic signatures in Post-COVID-19 include taurine, glutamine, alpha-Ketoglutaric acid, and LysoPC a C16:0. This study highlights the potential of integrating ML and XAI for a fine-grained description in metabolomics research, offering a more detailed understanding of metabolic anomalies in COVID-19 and Post-COVID-19 conditions.

Keywords:  COVID-19; explainable artificial intelligence (XAI); long Covid; machine learning (ML); metabolomics; post-COVID-19

DOI:  https://doi.org/10.3389/fmolb.2024.1429281
Pathophysiology. 2024 Aug 28. 31(3): 436-457

Persistent Post COVID-19 Endothelial Dysfunction and Oxidative Stress in Women.

Natalya Semenova, Ekaterina Vyrupaeva, Sergey Kolesnikov, Marina Darenskaya, Olga Nikitina, Lyubov Rychkova, Liubov Kolesnikova.

  The assessment of endothelial dysfunction and free radical homeostasis parameters were performed in 92 women, aged 45 to 69 years, divided into the following groups: women without COVID-19 (unvaccinated, no antibodies, control); women with acute phase of COVID-19 infection (main group, COVID-19+); 12 months post COVID-19+; women with anti-SARS-CoV-2 IgG with no symptoms of COVID-19 in the last 12 months (asymptomatic COVID-19). Compared to the control, patients of the main group had lower glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, decreased advanced glycation end products (AGEs) level, higher glutathione reductase (GR) activity, and higher glutathione S transferases pi (GSTpi), thiobarbituric acid reactants (TBARs), endothelin (END)-1, and END-2 concentrations (all p ≤ 0.05). The group with asymptomatic COVID-19 had lower 8-OHdG and oxidized glutathione (GSSG) levels, decreased total antioxidant status (TAS), and higher reduced glutathione (GSH) and GSH/GSSG levels (all p ≤ 0.05). In the group COVID-19+, as compared to the group without clinical symptoms, we detected lower GPx and SOD activities, decreased AGEs concentration, a higher TAS, and greater GR activity and GSTpi and TBARs concentrations (all p ≤ 0.05). The high content of lipid peroxidation products 12 months post COVID-19+, despite decrease in ENDs, indicates long-term changes in free radical homeostasis. These data indicate increased levels of lipid peroxidation production contribute, in part, to the development of free radical related pathologies including long-term post COVID syndrome.

Keywords:  COVID-19; antioxidant status; endothelial dysfunction; menopause; oxidative stress; post-COVID

DOI:  https://doi.org/10.3390/pathophysiology31030033
Int J Biol Macromol. 2024 Sep 23. pii: S0141-8130(24)06685-6. [Epub ahead of print]280(Pt 3): 135876

Duck hepatitis A virus 1-encoded 2B protein disturbs ion and organelle homeostasis to promote NF-κB/NLRP3-mediated inflammatory response.

Sai Mao, Xinghong Liu, Dandan Wu, Zhilong Zhang, Di Sun, Xumin Ou, Juan Huang, Ying Wu, Qiao Yang, Bin Tian, Shun Chen, Mafeng Liu, Dekang Zhu, Shaqiu Zhang, Xinxin Zhao, Yu He, Zhen Wu, Renyong Jia, Mingshu Wang, Anchun Cheng.

  Previous studies by our group and others have highlighted the critical role of hyperinflammation in the pathogenicity of duck hepatitis A virus 1 (DHAV-1), an avian picornavirus that has caused significant devastation in the duck industry worldwide for decades. However, the precise mechanisms by which DHAV-1 infection regulates the inflammatory responses, particularly the production of IL-1β, remain poorly understood. In this study, we demonstrate that DHAV-1 infection triggers NF-κB- and NLRP3 inflammasome-mediated IL-1β production. Mechanistically, DHAV-1 infection, particularly its replication and translation, disrupts cellular homeostasis of Ca2+, K+, ROS and cathepsin, which act cooperatively as assembly signals for NLRP3 inflammasome activation. By screening DHAV-1-encoded proteins, we identified that the viroporin 2B dominates NF-κB as well as NLRP3 inflammasome activation. Mutation analysis revealed that I43 within the 2B protein is the key amino acid for Ca2+ mobilization and subsequent activation of NF-κB transcriptional activity and NLRP3 inflammasome. Moreover, DHAV-1 infection and the 2B protein activate the MAVS- and MyD88-NF-κB pathways by relay, providing the necessary priming signals for NLRP3 inflammasome activation. In summary, our findings elucidate a mechanism through which DHAV-1 triggers inflammatory responses via NF-κB/NLRP3 inflammasome activation, offering new perspectives on DHAV-1 pathogenesis and informing the development of targeted anti-DHAV-1 treatments.

Keywords:  2B protein; Duck hepatitis A virus 1; Intracellular dyshomeostasis; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135876
mBio. 2024 Sep 26. e0219224

Transition metals and oxidation reactions trigger stargate opening during the initial stages of the replicative cycle of the giant Tupanvirus.

Juliana R Cortines, Charles M Bridges, Sundharraman Subramanian, Jason R Schrad, Glauber R S Araújo, Gabriel Henrique Pereira Nunes, Juliana Dos Santos Oliveira, Victor Alejandro Essus, Jônatas S Abrahão, Simon White, Kristin N Parent, Carolyn Teschke.

  Tupanviruses, members of the family Mimiviridae, infect phagocytic cells. Particle uncoating begins inside the phagosome, with capsid opening via the stargate. The mechanism through which this opening takes place is unknown. Once phagocytized, metal ion flux control and ROS are induced to inactivate foreign particles, including viruses. Here, we studied the effect of iron ions, copper ions, and H2O2 on Tupanvirus particles. Such treatments induced stargate opening in vitro, as observed by different microscopy techniques. Metal-treated viruses were found to be non-infectious, leading to the hypothesis that stargate opening likely resulted in the release of the viral seed, which is required for infection initiation. To the best of our knowledge, this is the first description of a giant virus capsid morphological change induced by transition metals and H2O2, which may be important to describe new virulence factors and capsid uncoating mechanisms.

Keywords:  ROS; Tupanvirus; copper; iron; nutritional immunity

DOI:  https://doi.org/10.1128/mbio.02192-24