bims-mevinf 2025-08-31 papers

Issue of 2025–08–31
six papers selected by

J Med Virol. 2025 Sep;97(9): e70578

Pexophagy Triggered by Enterovirus 71 Modulates the Production of Pro-Inflammatory Cytokines Through Cholesterol Accumulation in Lysosomes.

Tai Yang, Guowei He, Lingbing Chen, Lili Deng, Meimei Ren, Qing Zhao, Yuan Xiong, Bo Wang.

Mounting evidence indicates that pexophagy plays a pivotal role in various physiological and pathological processes. However, the crosstalk between pexophagy and enterovirus 71 (EV71) replication remains to be illustrated. The study aims to explore the molecular mechanisms and pathogenesis underlying the role of pexophagy in EV71 infection. In this study, our findings confirm and extend previous observations that autophagy facilitates EV71 replication. Next, we present strong novel evidence that EV71 replication can trigger excessive hydrogen peroxide in peroxisomes by mislocalization of peroxisomal catalase, leading to pexophagy. Moreover, our data indicate that dysfunctional peroxisomes elicit cholesterol accumulation in lysosomes, contributing to upregulated level of production of pro-inflammatory cytokines. Collectively, our study demonstrates that pexophagy may act as a new candidate player involved in the pathogenesis of EV71 infection via regulating oxidative stress status and inflammation, which provides a solid basis for the development of novel antivirus treatment.

Keywords: cholesterol; enterovirus 71; inflammatory cytokine; oxidative stress; pexophagy

DOI: https://doi.org/10.1002/jmv.70578

Front Cell Infect Microbiol. 2025 ;15 1625928

Ferroptosis and mitochondrial ROS are central to SARS-CoV-2-induced hepatocyte death.

Cintia Cevallos, Patricio Jarmoluk, Franco Sviercz, Rosa Nicole Freiberger, Cynthia Alicia Marcela López, M Victoria Delpino, Jorge Quarleri.

Background: Although COVID-19 primarily affects the respiratory tract, liver injury has been increasingly reported in infected individuals. The mechanisms by which SARS-CoV-2 induces hepatocyte damage remain poorly understood. Given the role of mitochondrial dysfunction, oxidative stress, and regulated cell death in COVID-19 pathogenesis, we investigated the impact of SARS-CoV-2 infection on hepatocytes using the Huh7.5 cell model.
Methods: Huh7.5 hepatocytes were infected with either the ancestral Wuhan (Wh) or Omicron (BA.5) variant of SARS-CoV-2. Viral replication was quantified via RT-qPCR, nucleocapsid protein detection, and infectious particle titration. Mitochondrial function was assessed through mitochondrial membrane potential (ΔΨm), mROS production, and mitophagy analysis. Lipid metabolism and regulated cell death (apoptosis, pyroptosis, ferroptosis) were evaluated by confocal microscopy and flow cytometry. The role of specific cell death pathways was probed using chemical inhibitors.
Results: Both SARS-CoV-2 variants efficiently infected Huh7.5 cells, with distinct replication kinetics. Infection induced mitochondrial fragmentation, elevated mROS levels, and lipid droplet accumulation. Ferroptosis was identified as a predominant mode of cell death, as evidenced by increased lipid peroxidation and the protective effect of ferrostatin-1. Expression of angiotensin-converting enzyme 2 (ACE2) and transferrin receptor 1 (TfR1), a ferroptosis marker and alternative viral entry receptor, was significantly upregulated post-infection in a variant-dependent manner. Additionally, mROS scavenging with MitoTEMPO impaired viral replication, underscoring the role of oxidative stress in the SARS-CoV-2 life cycle.
Conclusions: SARS-CoV-2 disrupts mitochondrial homeostasis and lipid metabolism in hepatocytes, promoting ferroptosis as a major contributor to virus-induced cytopathology. These findings suggest that ferroptosis may play a central role in COVID-19-related liver injury and identify mitochondrial ROS and iron metabolism as potential therapeutic targets.

Keywords: COVID-19; SARS-CoV-2; ferroptosis; hepatocytes; lipid metabolism; mitochondrial ROS; regulated cell death; transferrin receptor

DOI: https://doi.org/10.3389/fcimb.2025.1625928

J Med Virol. 2025 Aug;97(8): e70563

Viral Reprogramming of Nucleotide Synthesis and Its Impact on Viral Infection.

Lara Dsouza, Zhilong Yang.

Nucleotides are the building blocks of DNA and RNA. They also play essential roles in various other biological processes, including protein glycosylation, ribosome biogenesis, and cytoskeletal function. The significance of the regulation of nucleotide metabolism has recently gained more attention in many physiological and pathological contexts, including viral infections that often reprogram host cell metabolism to support viral replication. However, whilst nucleotides have long been known to be important for viral nucleic acid synthesis, the molecular mechanisms undertaken by viruses to regulate nucleotide synthesis are only beginning to be understood. In this review, we present a comprehensive analysis of nucleotide regulation by upstream growth factor signaling mechanisms in various families of RNA and DNA viruses, such as herpesviruses, poxviruses, influenza viruses, and coronaviruses. We place a primary emphasis on discussing the signaling pathways as the regulatory mechanisms and highlight the gaps in understanding the mechanistic details. We underscore recent research that investigates the roles of different viral factors in modulating nucleotide metabolism in the infections of DNA and RNA viruses. Finally, we discuss the emerging area of inquiry that explores the relationship between nucleotide metabolism and immune regulation. A thorough understanding of how nucleotides are regulated during viral infections is essential for developing novel effective therapeutic strategies against these viruses.

Keywords: antiviral immune responses; nucleotide metabolism; purine; pyrimidine; signaling; viral infection; virus

DOI: https://doi.org/10.1002/jmv.70563

Viruses. 2025 Jul 28. pii: 1052. [Epub ahead of print]17(8):

The HCV-Dependent Inhibition of Nrf1/ARE-Mediated Gene Expression Favours Viral Morphogenesis.

Olga Szostek, Patrycja Schorsch, Daniela Bender, Mirco Glitscher, Eberhard Hildt.

The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation-factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny.

Keywords: cholesterol; hepatitis C virus (HCV); nuclear factor erythroid 2 related factor-1 (Nrf1); nuclear factor erythroid 2 related factor-2 (Nrf2); small Maf proteins (sMaf)

DOI: https://doi.org/10.3390/v17081052

Mar Drugs. 2025 Jul 24. pii: 297. [Epub ahead of print]23(8):

An Oncolytic Vaccinia Virus Expressing Aphrocallistes Vastus Lectin Modulates Hepatocellular Carcinoma Metabolism via ACSS2/TFEB-Mediated Autophagy and Lipid Accumulation.

Qiang Wang, Simeng Zhou, Yin Wang, Yajun Gao, Yanrong Zhou, Ting Ye, Gongchu Li, Kan Chen.

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4-5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41-63% higher extracellular glucose and 33-34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC.

Keywords: ACSS2; Aphrocallistes vastus lectin; autophagy; oncolytic vaccinia virus

DOI: https://doi.org/10.3390/md23080297

JCI Insight. 2025 Aug 22. pii: e187680. [Epub ahead of print]10(16):

Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma.

Taewook Kang, Young-Kwang Usherwood, Julie A Reisz, Sukrut C Kamerkar, Rachel Culp-Hill, Owen M Wilkins, Andreia F Verissimo, Fred W Kolling, Anton M Hung, Shawn C Musial, Pamela C Rosato, Angelo D'Alessandro, Henry N Higgs, Edward J Usherwood.

T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and oxidative phosphorylation. Both groups had improved primary and memory recall responses following infection with murine gammaherpesvirus-68. However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, CD8+ T cell populations after B cell lymphoma challenge were smaller in both groups, resulting in poorer protection, which was rescued by glutamine and acetate supplementation. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.

Keywords: Adaptive immunity; Immunology; Immunotherapy; Metabolism

DOI: https://doi.org/10.1172/jci.insight.187680