bims-mevinf 2025-02-16 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–02–16
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Starve a cold or feed a fever? Identifying cellular metabolic changes following infection and exposure to SARS-CoV-2.
Recent advances in nutritional metabolism studies on SARS-CoV-2 infection.
Oxidative Stress Enhances Rubella Virus Infection in Immortalized Human First-Trimester Trophoblasts.
Metabolomic profile of severe COVID-19 and a signature predictive of progression towards severe disease status: a prospective cohort study (METCOVID).
DHODH inhibitors: What will it take to get them into the clinic as antivirals?
Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway.
SARS-CoV-2 S, M, and E Structural Glycoproteins Differentially Modulate Endoplasmic Reticulum Stress Responses.

PLoS One. 2025 ;20(2): e0305065

Starve a cold or feed a fever? Identifying cellular metabolic changes following infection and exposure to SARS-CoV-2.

Emma K Loveday, Hope Welhaven, Ayten Ebru Erdogan, Kyle S Hain, Luke F Domanico, Connie B Chang, Ronald K June, Matthew P Taylor.

Viral infections induce major shifts in cellular metabolism elicited by active viral replication and antiviral responses. For the virus, harnessing cellular metabolism and evading changes that limit replication are essential for productive viral replication. In contrast, the cellular response to infection disrupts metabolic pathways to prevent viral replication and promote an antiviral state in the host cell and neighboring bystander cells. This competition between the virus and cell results in measurable shifts in cellular metabolism that differ depending on the virus, cell type, and extracellular environment. The resulting metabolic shifts can be observed and analyzed using global metabolic profiling techniques to identify pathways that are critical for either viral replication or cellular defense. SARS-CoV-2 is a respiratory virus that can exhibit broad tissue tropism and diverse, yet inconsistent, symptomatology. While the factors that determine the presentation and severity of SARS-CoV-2 infection remain unclear, metabolic syndromes are associated with more severe manifestations of SARS-CoV-2 disease. Despite these observations a critical knowledge gap remains between cellular metabolic responses and SARS-CoV-2 infection. Using a well-established untargeted metabolomics analysis workflow, we compared SARS-CoV-2 infection of human lung carcinoma cells. We identified significant changes in metabolic pathways that correlate with either productive or non-productive viral infection. This information is critical for characterizing the factors that contribute to SARS-CoV-2 replication that could be targeted for therapeutic interventions to limit viral disease.

DOI: https://doi.org/10.1371/journal.pone.0305065
Infect Med (Beijing). 2025 Mar;4(1): 100162

Recent advances in nutritional metabolism studies on SARS-CoV-2 infection.

Yufen Jiang, Linle Xu, Xuexing Zheng, Hongbo Shi.

  In the context of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration of viral infection mechanisms and in searching for therapeutic strategies. This paper summarizes the interrelationships between carbohydrate, lipid, and amino acid metabolism and COVID-19 infection, discussing their roles in infection progression. SARS-CoV-2 infection leads to insulin resistance and increased glycolysis, reducing glucose utilization and shifting metabolism to use fat as an energy source. Fat is crucial for viral replication, and imbalances in amino acid metabolism may interfere with immune regulation. Consequently, metabolic changes such as hyperglycemia, hypolipidemia, and deficiency of certain amino acids following SARS-CoV-2 infection can contribute to progression toward severe conditions. These metabolic pathways not only have potential value in prediction and diagnosis but also provide new perspectives for the development of therapeutic strategies. By monitoring metabolic changes, infection severity can be predicted early, and modulating these metabolic pathways may help reduce inflammatory responses, improve immune responses, and reduce the risk of thrombosis. Research on the relationship between metabolism and SARS-CoV-2 infection provides an important scientific basis for addressing the global challenge posed by COVID-19, however, further studies are needed to validate these findings and provide more effective strategies for disease control.

Keywords:  Amino acid metabolism; Carbohydrate metabolism; Lipid metabolism; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.imj.2025.100162
Int J Mol Sci. 2025 Jan 25. pii: 1041. [Epub ahead of print]26(3):

Oxidative Stress Enhances Rubella Virus Infection in Immortalized Human First-Trimester Trophoblasts.

Quang Duy Trinh, Kazuhide Takada, Ngan Thi Kim Pham, Chika Takano, Takahiro Namiki, Shun Ito, Yoshinori Takeda, Shoko Okitsu, Hiroshi Ushijima, Satoshi Hayakawa, Shihoko Komine-Aizawa.

  Rubella infection (RuV) during early pregnancy is a known cause of congenital rubella syndrome (CRS). However, the mechanisms by which the virus crosses the placenta and infects the fetus are not fully understood. It has been known that various kinds of cell stresses can occur during the placenta formation. Previously, we demonstrated that low-glucose-induced endoplasmic reticulum stress could drastically enhance RuV infection in immortalized human first-trimester trophoblast cells. In this study, we investigated the roles of oxidative stress in RuV infection in these cells. Oxidative stress was induced in Swan.71 cells by culturing them in medium containing hydrogen peroxide (H2O2) in various concentrations and durations (50 µM or 100 µM for 24 h, or 150 µM for 1 h). RuV infection with a clinical strain was performed 24 h post-treatment, and capsid proteins were visualized at 24 and 48 h post-infection (hpi) using flow cytometry (FCM) and fluorescence microscopy (IF), respectively. The findings demonstrated that oxidative stress significantly enhanced RuV infection, as evidenced by FCM analysis, showing a twofold increase in infection rate, and confirmed by IF assay. Additionally, significantly increased intracellular viral replication was observed at 3 dpi. These findings suggest that oxidative stress during early pregnancy may promote the maternal-to-fetal transmission of rubella, contributing to the development of CRS.

Keywords:  CRS; ER stress; congenital rubella syndrome; flow cytometry; infection; oxidative stress; placenta; pregnancy; rubella; susceptibility; trophoblast

DOI:  https://doi.org/10.3390/ijms26031041
Sci Rep. 2025 Feb 10. 15(1): 4963

Metabolomic profile of severe COVID-19 and a signature predictive of progression towards severe disease status: a prospective cohort study (METCOVID).

Roger Mallol, Alexander Rombauts, Gabriela Abelenda-Alonso, Carlota Gudiol, Marc Balsalobre, Jordi Carratalà.

  Profound metabolomic alterations occur during COVID-19. Early identification of the subset of hospitalised COVID-19 patients at risk of developing severe disease is critical for optimal resource utilization and prompt treatment. This work explores the metabolomic profile of hospitalised adult COVID-19 patients with severe disease, and establishes a predictive signature for disease progression. Within 48 hours of admission, serum samples were collected from 148 hospitalised patients for nuclear magnetic resonance (NMR) spectroscopy. Lipoprotein profiling was performed using the 1H-NMR-based Liposcale test, while low molecular weight metabolites were analysed using one-dimensional Carr-Purcell-Meiboom-Gill pulse spectroscopy and an adaptation of the Dolphin method for lipophilic extracts. Severe COVID-19, per WHO's Clinical Progression Scale, was characterized by altered lipoprotein distribution, elevated signals of glyc-A and glyc-B, a shift towards a catabolic state with elevated levels of branched-chain amino acids, and accumulation of ketone bodies. Furthermore, COVID-19 patients initially presenting with moderate disease but progressing to severe stages exhibited a distinct metabolic signature. Our multivariate model demonstrated a cross-validated AUC of 0.82 and 72% predictive accuracy for severity progression. NMR spectroscopy-based metabolomic profiling enables the identification of moderate COVID-19 patients at risk of disease progression, aiding in resource allocation and early intervention.

Keywords:  COVID-19; Metabolomics; NMR; Prognosis; SARS-CoV-2; Severity; Spectroscopy

DOI:  https://doi.org/10.1038/s41598-025-87288-x
Antiviral Res. 2025 Feb 10. pii: S0166-3542(25)00025-7. [Epub ahead of print]236 106099

DHODH inhibitors: What will it take to get them into the clinic as antivirals?

Anna Luganini, Donatella Boschi, Marco L Lolli, Giorgio Gribaudo.

  The emergence of new human viruses with epidemic or pandemic potential has reaffirmed the urgency to develop effective broad-spectrum antivirals (BSAs) as part of a strategic framework for pandemic prevention and preparedness. To this end, the host nucleotide metabolic pathway has been subject to intense investigation in the search for host-targeting agents (HTAs) with potential BSA activity. In particular, human dihydroorotate dehydrogenase (hDHODH), a rate-limiting enzyme in the de novo pyrimidine biosynthetic pathway, has been identified as a preferential target of new HTAs. Viral replication in fact relies on cellular pyrimidine replenishment, making hDHODH an ideal HTA target. The depletion of the host pyrimidine pool that ensues the pharmacological inhibition of hDHODH activity elicits effective BSA activity through three distinct mechanisms: it blocks viral DNA and RNA synthesis; it activates effector mechanisms of the host innate antiviral response; and it mitigates the virus-induced inflammatory response. However, despite the spectacular results obtained in vitro, the hDHODH inhibitors examined as mono-drug therapies in animal models of human viral infections and in clinical trials have produced disappointing levels of overall antiviral efficacy. To overcome this inherent limitation, pharmacological strategies based on multi-drug combination treatments should be considered to enable efficacy of hDHODH-targeted antiviral therapies. Here, we review the state-of-the-art of antiviral applications of hDHODH inhibitors, discuss the challenges that have emerged from their testing in animal models and human clinical trials and consider how they might be addressed to advance the development of hDHODH inhibitors as BSA for the treatment of viral diseases.

Keywords:  Broad-spectrum antivirals; Combination treatments; DHODH; Host-targeting agents; Pyrimidine salvage pathway; de novo pyrimidine biosynthesis pathway

DOI:  https://doi.org/10.1016/j.antiviral.2025.106099
Open Life Sci. 2025 ;20(1): 20220951

Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway.

Chengrong Huang, Hao Zhang, Jing Wang, Jianfei Li, Qian Liu, Qiyin Zong, Yunyun Zhang, Qin Wang, Qiang Zhou.

  A growing body of evidence has shown that hepatitis B surface antigen (HBsAg) mutations can influence the occurrence of occult hepatitis B infection (OBI), particularly amino acid substitutions in small hepatitis B surface proteins (SHBs). The mechanistic basis for these results, however, remains unclear. This study was designed to explore the potential impact and mechanisms of OBI-related SHBs mutations on serum HBsAg. Huh7 and HepG2 cells were transfected with plasmids encoding wild-type (WT) or OBI-related SHB mutation-containing sequences, after which a chemiluminescence approach was used to detect HBsAg levels in cell culture supernatants. Western blotting was further used to assess HBsAg and endoplasmic reticulum stress (ERS)-related protein levels in lysates prepared from these cells, while the localization of HBsAg within cells was assessed via immunofluorescent staining. Cells transfected with OBI-related SHB mutation-encoding plasmids exhibited lower supernatant HBsAg levels than cells transfected with WT plasmids. Intracellular and extracellular HBsAg levels in these mutant plasmid-transfected cells were lower relative to those for WT plasmid-transfected cells, and HBsAg accumulation within the ER was detected via immunofluorescent staining in cells transfected with OBI-related SHB mutation-encoding plasmids, ERS-related protein content was also significantly increased in mutant plasmid-transfected cells as compared to those in the WT group. These results suggest that proteins harboring OBI-related mutations may tend to accumulate in the ER, thereby triggering an ERS response and impairing the transcription and translation of HBsAg via the activation of the unfolded protein response and ER-associated protein degradation pathway. These effects ultimately reduce the overall assembly of HBV virions in the ER and their associated secretion.

Keywords:  ER-associated protein degradation; endoplasmic reticulum stress; hepatitis B surface antigen; mutation; occult hepatitis B virus infection

DOI:  https://doi.org/10.1515/biol-2022-0951
Int J Mol Sci. 2025 Jan 26. pii: 1047. [Epub ahead of print]26(3):

SARS-CoV-2 S, M, and E Structural Glycoproteins Differentially Modulate Endoplasmic Reticulum Stress Responses.

Wejdan Albalawi, Jordan Thomas, Farah Mughal, Aurelia Kotsiri, Kelly J Roper, Abdullateef Alshehri, Matthew Kelbrick, Georgios Pollakis, William A Paxton.

  We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells.

Keywords:  HIV-1 LTR; SARS-CoV-2; endoplasmic reticulum (ER) stress; structural proteins

DOI:  https://doi.org/10.3390/ijms26031047