bims-mevinf 2025-12-21 papers

Front Microbiol. 2025 ;16 1683365

Metabolic reprogramming by pseudorabies virus: nucleotide metabolism as a central vulnerability for viral replication and pathogenesis.

Xiaoyong Chen, Qingsen Wang, Xi Chen.

Pseudorabies virus (PRV), a neurotropic alphaherpesvirus, causes severe neurological and reproductive disorders in swine, posing substantial threats to the global swine industry and emerging as a zoonotic concern. Viral metabolic reprogramming is a conserved strategy to support replication, yet the metabolic landscape of PRV infection remains incompletely defined. Here, we employed ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics combined with multivariate statistical analysis to systematically profile metabolic changes in PRV-infected porcine kidney PK-15 cells. Unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed a striking separation of metabolic phenotypes between PRV-infected (48 hpi) and control (0 hpi) cells, with the first principal component accounting for >73% of total variance, confirming significant metabolic reprogramming upon infection. We identified 1,634 and 925 differential metabolites in ESI+ and ESI- modes, respectively, with hierarchical cluster analysis revealing distinct signatures: amino acids and heterocyclic compounds were predominantly upregulated, while glycerophospholipids (GPs) were markedly downregulated. KEGG pathway enrichment analysis highlighted key perturbed networks underlying PRV pathogenesis: glycerophospholipid metabolism was targeted to modulate membrane dynamics for viral egress and dampen innate immune signaling; aminoacyl-tRNA and nucleotide sugar metabolism were enhanced to support viral protein synthesis and glycosylation. Notably, nucleotide metabolism was profoundly upregulated, with increased levels of adenosine, guanosine, adenine, and xanthosine. Transcriptomic validation (GSE8676 dataset) and qRT-PCR confirmed time-dependent upregulation of critical purine biosynthesis genes, including IMPDH, GMPS, ADSS2, GART, and ATIC, peaking at 48 hpi. These findings demonstrate that PRV orchestrates multifaceted metabolic takeover, with nucleotide metabolism emerging as a key vulnerability. Targeting this pathway may offer novel strategies to disrupt PRV replication, providing insights into viral-host metabolic crosstalk and antiviral development.

Keywords: LC–MS; PK-15 cells; metabolites; nucleotide metabolism; pseudorabies virus

DOI: https://doi.org/10.3389/fmicb.2025.1683365

Front Microbiol. 2025 ;16 1690133

Metabolic hijacking styles: a review of how viral life cycles dictate glucose metabolism reprogramming.

Ziyi Bie, Yixing Tan, Chun Ye, Ke Wei.

Viral infection profoundly reprograms host glucose metabolism to support replication. This review proposes a "Sprint vs. Marathon" framework to explain how viral life cycles shape distinct metabolic hijacking styles. Acute RNA viruses employ a rapid, high-intensity "Sprint" strategy, aggressively activating glycolysis through pathways such as PI3K/Akt and HIF-1α. In contrast, chronic and latent viruses adopt a sustained "Marathon" strategy, subtly modulating glycolytic enzymes, glucose transporters, and survival pathways including NF-κB and mTOR. Understanding these divergent metabolic programs provides new insight into viral pathogenesis and highlights opportunities for developing host-directed antiviral therapies.

Keywords: glucose metabolism; glycolytic enzymes; host–virus interaction; metabolic reprogramming; viral infection

DOI: https://doi.org/10.3389/fmicb.2025.1690133

Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2509118122

MTHFR allele and one-carbon metabolic profile predict severity of COVID-19.

IMPACC Network

While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are thousands of new hospitalizations and hundreds of deaths per week in the United States, many of whom develop long COVID. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here, we report an untargeted, longitudinal plasma metabolomics study of COVID-19 patients. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. Targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a preexisting contributor to disease trajectory-patients that show aberrant one-carbon metabolite levels and that are homozygous for the MTHFR C677T, have higher incidence of severe COVID. Our results raise the possibility that MTHFR variant status may inform precision COVID-19 treatment strategies.

Keywords: MTHFR; genetic predisposition; long COVID; plasma metabolic signature; severe COVID risk factors

DOI: https://doi.org/10.1073/pnas.2509118122

bioRxiv. 2025 Nov 27. pii: 2025.11.26.690702. [Epub ahead of print]

Homotypic endoplasmic reticulum membrane tethering is critical for flavivirus replication.

Jonathan Einterz Owen, Cheyanne Lee Bemis, Qingyi Wang, Ambarish C Varadan, Jacob W Vander Velden, Laura Andačić, Olus Uyar, Mansi Gupta, Christopher D Scharer, Laurent Chatel-Chaix, Pietro Scaturro, Mehul S Suthar, Christopher J Neufeldt.

Flaviviruses (genus Orthoflavivirus ) are arthropod-borne viruses which cause approximately 400 million annual global infections in humans. Flavivirus infection requires cellular machinery to facilitate replication and spread. All known flaviviruses replicate in association with the host endoplasmic reticulum (ER), where genome replication is confined within virus-induced ER invaginations called viral replication organelles (vROs). Despite the central role of these structures during flavivirus infection, the mechanisms underlying vRO biogenesis remain undefined - particularly the membrane rearrangements required for their formation. In this work, we report a conserved role for a cellular ER remodeling protein, atlastin-2 (ATL2), in the organization of vROs within infected cells. Using confocal and electron microscopy, we show that ATL2 depletion leads to a reduction in vRO spatial distribution in flavivirus-infected cells. Changes in vRO distribution corresponded with a decrease in virus production and robust induction of innate immune responses. We also demonstrate that ATL2 accumulates in areas of vRO formation during flavivirus infection. Critically, mutational analysis showed that a tethering-competent but fusion-defective ATL2 mutant was sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells. Finally, inhibition of ATL2 activity using synthetic peptides significantly reduced DENV replication in both immortalized and human primary cells, suggesting a possible avenue for targeting host ER functions to limit flavivirus replication. Taken together, these results show that membrane tethering plays a critical and conserved role in flavivirus infection, functioning to organize membranes for vRO biogenesis and limit cellular immune activation. Importantly, we provide evidence that ATL2-mediated membrane organization can be targeted to inhibit viral replication.

DOI: https://doi.org/10.1101/2025.11.26.690702

Eur J Immunol. 2025 Dec;55(12): e70087

Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism.

Amsterdam UMC COVID‐19 Biobank

Severe COVID-19 is an immunological disorder characterized by excessive immune activation following infection with SARS-CoV-2, which typically occurs around the time of seroconversion. Anti-spike IgG of critically ill COVID-19 patients induces excessive inflammation by activation of Fc gamma receptors (FcγRs) on human alveolar macrophages, leading to tissue damage, pulmonary edema, and coagulopathy. While metabolic reprogramming of immune cells is critical for the induction of inflammatory responses, still little is known about the metabolic pathways that are involved in COVID-19-specific hyperinflammation. In this study, we identified that anti-spike IgG immune complexes (ICs) induce rapid metabolic reprogramming of alveolar macrophages, which is essential for the induction of inflammation. Through functional inhibition, we identified that glycolysis, fatty acid synthesis, and pentose phosphate pathway (PPP) activation are critical for anti-spike IgG-induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti-spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti-spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID-19. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID-19 and related diseases.

Keywords: COVID‐19; antibodies; immunometabolism; macrophage

DOI: https://doi.org/10.1002/eji.70087

Virol J. 2025 Dec 17.

Glucose-6-phosphate dehydrogenase deficiency facilitates hepatitis E virus entry and aggravates liver injury.

Dongxue Chen, Xiaoxia Hu, Yuanwen Xue, Fuwen Xia, Min Li, Jiankun Liu, Fen Huang.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) is an common enzyme deficiency disease, inducing hemolysis, hyperbilirubinemia, and jaundice, as well as liver dysfunction, in approximately 400 million patients. Patients with G6PDd are more susceptible to viruses infection than those without. However, the incidence and severity of hepatitis E virus (HEV) infection in patients with G6PDd are largely unknown.
METHODS: The prevalence of HEV in patients with G6PDd was investigated. Susceptibility to HEV was evaluated in a hepatoma cell line with G6PD knockdown, and the interaction between HEV and G6PD was assessed.
RESULTS: The prevalence of HEV infection was higher in patients with G6PDd (23.8%, 25/105) than in patients with normal G6PD levels (0.65%, 2/307), indicating that patients with G6PDd are susceptible to HEV infection. Higher rates of hyperbilirubinemia (64% vs. 36.25%) and pneumonia (28% vs. 12.5%) were observed in HEV-infected patients with G6PDd than in patients with normal G6PD values. G6PD knockdown facilitated HEV entry and aggravated oxidative stress with the significant inhibition of glutathione to benefit viral replication but was restricted by NADPH reduction. Co-IP and colocation assays revealed that HEV ORF3 interacted with G6PD. HEV infection stimulated the expression of G6PD in a manner dependent on nuclear factor E2-related factor 2 activation. Consequently, severe apoptosis was observed in HEV-infected cells with G6PD knockdown.
CONCLUSIONS: Patients with G6PDd are susceptible to HEV infection. The facilitation of HEV entry and aggravation of oxidative stress may contribute to HEV susceptibility in patients with G6PDd and severe disease.

Keywords: G6PDd; HEV infection; Oxidative stress; Severity; Susceptibility

DOI: https://doi.org/10.1186/s12985-025-03031-y