bims-mevinf 2025-03-09 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–03–09
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Human adenovirus serotype 5 infection dysregulates cysteine, purine, and unsaturated fatty acid metabolism in fibroblasts.
HCV NS3/4A protease relocalizes CCTα to viral replication sites, enhancing phosphatidylcholine synthesis and viral replication.
Involvement of oxidative stress in post-acute sequelae of COVID-19: clinical implications.
Apatinib inhibits HTNV by stimulating TFEB-driven lysosome biogenesis to degrade viral protein.
A mitochondria targeted hydrogen peroxide fluorescent probe for monitoring oxidative stress during influenza virus infection.
Indoleamine 2,3-dioxygenase 1 drives epithelial cells ferroptosis in influenza-induced acute lung injury.
Metabolomic and lipoproteomic differences and similarities between COVID-19 and other types of pneumonia.
Disruptions in serotonin- and kynurenine pathway metabolism in post-COVID: biomarkers and treatment.
The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects.
Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae.
Exploring the metabolic alterations in cervical cancer induced by HPV oncoproteins: From mechanisms to therapeutic targets.

FASEB J. 2025 Mar 15. 39(5): e70411

Human adenovirus serotype 5 infection dysregulates cysteine, purine, and unsaturated fatty acid metabolism in fibroblasts.

Bailey-J C Sanchez, Rudy M Ortiz, Juris A Grasis.

  Viral infections can cause cellular dysregulation of metabolic reactions. Viruses alter host metabolism to meet their replication needs. The impact of viruses on specific metabolic pathways is not well understood, even in well-studied viruses, such as human adenovirus. Adenoviral infection is known to influence cellular glycolysis and respiration; however, global effects on overall cellular metabolism in response to infection are unclear. Furthermore, few studies have employed an untargeted approach, combining emphasis on viral dosage and infection. To address this, we employed untargeted metabolomics to quantify the dynamic metabolic shifts in fibroblasts infected with human adenovirus serotype 5 (HAdV-5) at three dosages (0.5, 1.0, and 2.0 multiplicity of infection [MOI]) and across 4 time points (6-, 12-, 24-, and 36-h post-infection [HPI]). The greatest differences in individual metabolites were observed at 6- and 12-h post-infection, correlating with the early phase of the HAdV-5 infection cycle. In addition to its effects on glycolysis and respiration, adenoviral infection downregulates cysteine and unsaturated fatty acid metabolism while upregulating aspects of purine metabolism. These results reveal specific metabolic pathways dysregulated by adenoviral infection and the associated dynamic shifts in metabolism, suggesting that viral infections alter energetics via profound changes in lipid, nucleic acid, and protein metabolism. The results revealed previously unconsidered metabolic pathways disrupted by HAdV-5 that can alter cellular metabolism, thereby prompting further investigation into HAdV mechanisms and antiviral targeting.

Keywords:  adenovirus; fibroblasts; mass spectrometry; metabolomics

DOI:  https://doi.org/10.1096/fj.202402726R
Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2419632122

HCV NS3/4A protease relocalizes CCTα to viral replication sites, enhancing phosphatidylcholine synthesis and viral replication.

Shamila Sarwar, Glenn Randall.

  Positive-sense single-stranded RNA [(+)RNA] viruses constitute more than one-third of all virus genera, including numerous pathogens of clinical significance. All (+)RNA viruses reorganize cellular membranes from organelles to establish replication compartments (RCs). These RCs are thought to form a platform for membrane-associated replicases, in addition to protecting the viral RNAs from cytosolic innate immune signaling and RNA-degradation machinery. Previous work demonstrated that three families of (+)RNA viruses, namely Bromoviridae, Picornaviridae, and Flaviviridae, commonly induce the accumulation of phosphatidylcholine (PC) at their RCs. This phenomenon suggests a potential avenue for a broad-spectrum antiviral strategy targeting PC metabolism. Our study elucidates three key observations: i) hepatitis C virus (HCV) infection prompts the relocalization of CCTα, the rate-limiting enzyme in PC synthesis, to the RCs; ii) the enhancement of PC synthesis is contingent upon the protease activity of the NS3/4A protein; and iii) utilizing click chemistry, we demonstrate that HCV infection stimulates de novo PC synthesis at the viral replication site through the Kennedy pathway. These findings provide significant insights into the manipulation of lipid metabolism by HCV during RC formation, a mechanism likely conserved across various (+)RNA virus families.

Keywords:  lipid synthesis; viral proteases; viral replication compartments

DOI:  https://doi.org/10.1073/pnas.2419632122
Redox Rep. 2025 Dec;30(1): 2471738

Involvement of oxidative stress in post-acute sequelae of COVID-19: clinical implications.

Paola Mayara Valente Coronel, Denise Caroline Luiz Soares Basilio, Isabelly Teixeira Espinoça, Kamylla Fernanda Souza de Souza, Nathalia Miranda Campos, Rafael Seiji Nakano Ota, Edgar Julian Paredes-Gamero, Danilo Wilhelm Filho, Ana Rita Coimbra Motta-Castro, Renata Trentin Perdomo, Eduardo Benedetti Parisotto.

  Oxidative stress (OS) plays a key role in the pathophysiology of COVID-19 and may be associated with sequelae after severe SARS-CoV-2 infection. This study evaluated OS and inflammation biomarkers in blood from individuals with post-acute sequelae of COVID-19 (PASC). 64 male and female participants were distributed into three groups: healthy individuals (n = 20), acute COVID-19 patients (symptoms for <3 weeks, n = 15), and PASC patients (symptoms for >12 weeks, n = 29). Analyses included inflammatory cytokines, myeloperoxidase (MPO) activity, and OS markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), gamma-glutamyl transferase (GGT), reduced glutathione (GSH), uric acid (UA), thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC). Individuals with PASC showed increased IL-6 and IL-8. Both COVID-19 groups exhibited decreased SOD and CAT. GST decreased only in the acute group. Elevated GGT and GSH were found in the PASC group. High UA levels were observed in PASC individuals. There were no changes in TBARS values ⁣⁣in the PASC group. However, PC concentrations were elevated only in this group. Correlations were identified between inflammatory markers and OS parameters. These findings suggest that individuals with PASC pronounced OS, which potentially exacerbates disease complications. Monitoring OS biomarkers could aid in patient prognosis and management.

Keywords:  SARS-CoV-2; antioxidants; chronic COVID syndrome; cytokines; inflammation; long-COVID; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1080/13510002.2025.2471738
Antiviral Res. 2025 Feb 26. pii: S0166-3542(25)00050-6. [Epub ahead of print]237 106124

Apatinib inhibits HTNV by stimulating TFEB-driven lysosome biogenesis to degrade viral protein.

Qikang Ying, Xiaoxiao Zhang, Tianle Gu, Junmei Zhang, Yuhang Dong, Wenjie Feng, Dongjing Li, Xingan Wu, Fang Wang.

  Hantaan Orthohantavirus (Hantaan virus, HTNV) infection causes hemorrhagic fever with renal syndrome (HFRS) in humans, posing a significant health threat. Currently, there are no long-lasting protective vaccines or specific antivirals available, creating an urgent need for effective antiviral treatments in the clinical management of HFRS. Given that viruses exploit multiple host factors for their replication, host-oriented inhibitors could offer promising therapeutic options. In our study, we screened a library of 2570 drugs and identified apatinib, a kinase inhibitor, as a potent suppressor of HTNV infection both in vitro and in vivo. Mechanistic studies revealed that apatinib exerts its antiviral effect by targeting transcription factor EB (TFEB). Specifically, apatinib inhibits the PI3K-Akt signaling pathway and reduces mTOR phosphorylation, which in turn downregulates TFEB phosphorylation. This facilitates the nuclear translocation of TFEB and enhances lysosomal function by upregulating the expression of lysosome-associated genes and promoting lysosome biogenesis. Consequently, there is an increase in lysosome-mediated viral nucleocapsid protein degradation. The ability of apatinib to stimulate this lysosome-driven antiviral mechanism presents a potential new therapeutic approach for viral infections and offers valuable insights into virus-host interactions during HTNV replication.

Keywords:  Drug repurpose; Hantaan virus (HTNV); Transcription factor EB (TFEB); Vascular endothelial growth factor receptor-2 (VEGFR2)

DOI:  https://doi.org/10.1016/j.antiviral.2025.106124
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Feb 21. pii: S1386-1425(25)00235-5. [Epub ahead of print]334 125929

A mitochondria targeted hydrogen peroxide fluorescent probe for monitoring oxidative stress during influenza virus infection.

Hao Chang, Jianing Wang, Yang Yang, Zhenyou Jiang, Yue Chen, Zhiqi Lao.

  Hydrogen peroxide (H2O2), an important marker of oxidative stress, plays a significant role in infectious diseases. Oxidative stress induced by influenza virus infection is intricately linked to the pathological processes of host cells. In this work, a fluorescent probe QLC1 based on the coumarin was developed for fluorescence imaging of mitochondrial H2O2 level in host cells during influenza virus infection. The self-immolative reaction of QLC1 triggered by H2O2 will lead to a 250-fold fluorescence enhance and the limit of detection was determined to be 0.176 μM. Using this probe, we monitored oxidative stress during influenza infection and identified a link between redox status and influenza virus replication.

Keywords:  Hydrogen peroxide; Influenza virus; Oxidative stress

DOI:  https://doi.org/10.1016/j.saa.2025.125929
Redox Biol. 2025 Feb 26. pii: S2213-2317(25)00085-0. [Epub ahead of print]81 103572

Indoleamine 2,3-dioxygenase 1 drives epithelial cells ferroptosis in influenza-induced acute lung injury.

Yongxin Zheng, Yu Zhang, Yubiao Chen, Xiumei Deng, Baiyun Liu, Qiang Xu, Chuyun Qian, Zhihui Zhang, Ke Wang, Yuan Zeng, Zhenting Liang, Ling Sang, Lingbo Nong, Xiaoqing Liu, Yonghao Xu, Yimin Li, Yongbo Huang.

  Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.

Keywords:  Acute lung injury; Acute respiratory distress syndrome; Indoleamine 2,3-dioxygenase 1; Influenza a virus; Iron accumulation; Nitrative stress; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2025.103572
Sci Rep. 2025 Mar 03. 15(1): 7507

Metabolomic and lipoproteomic differences and similarities between COVID-19 and other types of pneumonia.

Veronica Ghini, Valentina Pecchioli, Tommaso Celli, Nunzia Boccia, Laura Bertini, Francesca Veneziani, Vieri Vannucchi, Paola Turano.

  COVID-19 infection has revealed significant effects on the human blood metabolome and lipoproteome, which have been coherently observed in different cohorts worldwide and across the various waves of SARS-CoV-2 pandemic. As one of the main clinical manifestations of COVID-19 is a severe acute respiratory illness, it is pertinent to explore whether this metabolic/lipoproteomic disturbance is associated with the respiratory symptoms. To this purpose we are here reporting comparative1H NMR analyses of the plasma of 252 COVID-19 patients and of patients with non-COVID-19 interstitial (24 individuals) or lobar (21 individuals) pneumonia, all matched by age, gender and disease severity. The analysis is based on 24 metabolites and 114 lipoprotein parameters. Several common traits are observed among the three groups, albeit with some peculiar features characteristic of each group. The main differences were observed between the lobar cases and all the others.

Keywords:  COVID-19; Lipoproteins; Metabolomics; Nuclear magnetic resonance (NMR); Pneumonia

DOI:  https://doi.org/10.1038/s41598-025-91965-2
Front Neurol. 2025 ;16 1532383

Disruptions in serotonin- and kynurenine pathway metabolism in post-COVID: biomarkers and treatment.

Carla P Rus.



Keywords:  5-hydroxytryptophan (5-HTP); KP metabolites; kynurenine pathway (KP); long COVID; post-COVID-syndrome (PCS); selective serotonin reuptake inhibitors (SSRIs); serotonin; tryptophan

DOI:  https://doi.org/10.3389/fneur.2025.1532383
J Pharm Anal. 2025 Jan;15(1): 101050

The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects.

Tong Wu, Miaorong Ji, Tian Li, Lianxiang Luo.

  Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), lung cancer, pulmonary fibrosis (PF), and the coronavirus disease 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.

Keywords:  Antioxidant mechanism; Ferroptosis; Iron metabolism; Lipid peroxidation; Respiratory diseases

DOI:  https://doi.org/10.1016/j.jpha.2024.101050
Science. 2025 Mar 07. 387(6738): eadq2509

Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae.

Xiaoqin Wei, Wei Qian, Harish Narasimhan, Ting Chan, Xue Liu, Mohd Arish, Samuel Young, Chaofan Li, In Su Cheon, Qing Yu, Gislane Almeida-Santos, Xiao-Yu Zhao, Eric V Yeatts, Olivia J Spear, Megan Yi, Tanyalak Parimon, Yinshan Fang, Young S Hahn, Timothy N J Bullock, Lindsay A Somerville, Mark H Kaplan, Anne I Sperling, Yun Michael Shim, Robert Vassallo, Peter Chen, Sarah E Ewald, Anja C Roden, Jianwen Que, Dianhua Jiang, Jie Sun.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

DOI: https://doi.org/10.1126/science.adq2509
Biochim Biophys Acta Rev Cancer. 2025 Mar 02. pii: S0304-419X(25)00034-4. [Epub ahead of print] 189292

Exploring the metabolic alterations in cervical cancer induced by HPV oncoproteins: From mechanisms to therapeutic targets.

Mrudula Gore, Shama Prasada Kabekkodu, Sanjiban Chakrabarty.

  The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.

Keywords:  Cellular-MYC; Fatty acid metabolism; Human papillomavirus; Hypoxia inducible factor 1α; Lactate dehydrogenase; Metabolic reprogramming; p53

DOI:  https://doi.org/10.1016/j.bbcan.2025.189292