bims-mevinf 2025-09-21 papers

Int J Biol Macromol. 2025 Sep 13. pii: S0141-8130(25)08220-0. [Epub ahead of print] 147663

Bovine viral diarrhea virus E2 targets SLC3A2 to modulate lipid peroxidation for replication advantage.

Di Wu, Faiz Ur Rehman, Jingru Zheng, Kaihui Yang, Chuanwen Jiang, Xiaowen Xu, Xinwei Yuan, Aizhen Guo.

Pestiviruses, part of the Flaviviridae family, are responsible for major livestock diseases such as bovine viral diarrhea, classical swine fever, and border disease. These infections lead to substantial economic losses worldwide. However, their pathogenesis remains incompletely understood, limiting the development of effective control strategies. In this study, we explored how bovine vial diarrhea virus (BVDV) regulate host lipid peroxidation (LPO) to support viral replication. We initially found that early infection with BVDV enhanced intracellular redox balance by upregulating the cystine/glutamate antiporter system xc- in Madin-Darby bovine kidney (MDBK) cells, thereby increasing glutathione (GSH) synthesis and glutathione peroxidase (GPX) activity. Consistently, Erastin2, a selective inhibitor of system xc-, induced LPO and suppressed BVDV replication. Further analysis identified SLC3A2, a subunit of system xc-, as a key regulator of redox homeostasis during infection. Both siRNA knockdown and CRISPR/Cas9 knockout of SLC3A2 significantly impaired viral replication. Co-immunoprecipitation and confocal microscopy revealed that BVDV E2 domain 3 subdomain III directly binds to the N-terminal region (amino acids 1-146) of SLC3A2. These findings uncover a novel viral strategy to suppress LPO via the E2-SLC3A2-GSH-GPX4 axis, offering new targets for antiviral intervention.

Keywords: Lipid peroxidation; Pestiviruses; SLC3A2

DOI: https://doi.org/10.1016/j.ijbiomac.2025.147663

Curr HIV Res. 2025 Sep 11.

Impact of HIV-1 Tat on FDFT1 Suppression, Changes in Cholesterol Level, and KSHV Replication in BCBL1 Cells.

Qiaozhen Liu, Xiaoying Chen, Dewen Liu, Yuting Zou, Weiling Yang, Ziyi Cao, Yao Ding, Weihang Ji, Na Xiao, Huaying Tang, Yan Jiang, Liandeng Wei, Yi Zeng.

INTRODUCTION: The present study investigated the molecular mechanism by which the transactivator of transcription (Tat) protein of Human Immunodeficiency Virus 1 (HIV-1) activates the replication cycle of Kaposi's Sarcoma-associated Herpesvirus (KSHV).
METHODS: BCBL-1 cells were initially infected with lentivirus overexpressing HIV-1 Tat. The relative mRNA expression of Farnesyl Diphosphate Farnesyltransferase 1 (FDFT1), HIV-1 Tat, KSHV Open Reading Frame 73 (ORF73), and KSHV Open Reading Frame 50 (ORF50) was quantified by real-time fluorescent quantitative Polymerase Chain Reaction (RT-qPCR). The cellular cholesterol levels were determined using a total cholesterol assay kit. BCBL-1 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) served as a positive control for the lytic replication of KSHV. The relative mRNA expression levels of HIV-1 Tat, FDFT1, KSHV ORF73, and KSHV ORF50 were subsequently evaluated in BCBL-1 cells following infection with lenti-viruses for FDFT1 overexpression or FDFT1-RNAi knockdown, and the cellular cholesterol content was quantified.
RESULTS: The findings revealed that HIV-1 Tat downregulated FDFT1 and upregulated the expression of KSHV ORF50 in BCBL-1 cells. FDFT1 overexpression upregulated the expression of the latency-associated gene, ORF73, of KSHV in BCBL-1 cells, while knockdown of FDFT1 upregulated the expression of genes associated with the lytic reactivation of KSHV. Infection with the HIV-1 lentivirus, which overexpresses Tat, as well as manipulation of FDFT1, significantly altered the cholesterol content in BCBL-1 cells.
CONCLUSION: The downregulation of FDFT1 by HIV-1 Tat modulates cellular cholesterol levels and is associated with KSHV replication in BCBL-1 cells.

Keywords: FDFT1; HIV-1; KSHV; cellular cholesterol content.; replication cycle; tat protein

DOI: https://doi.org/10.2174/011570162X371221250630105858

Vet Res. 2025 Sep 19. 56(1): 175

Copper-mediated MAM regulation of the NF-κB signalling pathway enhances Seneca Valley virus replication in PK-15 cells.

Xiaoli Wu, Song Zhu, Min Li, Zhiwen Xu, Ling Zhu, Junliang Deng, Huidan Deng.

Seneca Valley virus (SVV) is known to cause vesicular disease in swine, presenting new challenges to the pig industry. Recent studies have investigated the relationship between disrupted copper ion homeostasis and viral replication, suggesting that copper dysregulation has a significant impact on the replication of various viruses. Research has also shown that mitochondria-associated endoplasmic reticulum membrane (MAM) and NF-κB are involved in the innate immune response triggered by viral infections. However, the exact mechanisms by which copper (Cu), MAM, and NF-κB affect SVV replication remain unclear. In this study, it was found that SVV induces an imbalance in copper homeostasis, leading to dynamic changes in MAM while inhibiting the NF-κB pathway. This inhibition results in decreased levels of IL-6, IL-1β, TNF-α, IFN-α, and IFNλ3. Furthermore, the disruption of copper homeostasis in SVV-infected PK-15 cells regulates the NF-κB pathway through MAM, promoting SVV replication. This research provides valuable insights into the regulation of copper metabolism during SVV infection and establishes a theoretical framework for understanding the pathogenesis and immune activation mechanisms associated with SVV.

Keywords: MAM; NF-κB pathway; SVV; copper homeostasis; innate immunity

DOI: https://doi.org/10.1186/s13567-025-01578-w

Emerg Microbes Infect. 2025 Sep 17. 2563067

In Vitro and Ex Vivo Evidences that Pharmacological Induction of the Hypoxia Response Pathway Efficiently Restricts Measles and Nipah Virus Infections.

Airborne RNA viruses of the Paramyxoviridae family are major human pathogens. These include measles virus (MeV) and Nipah virus (NiV), the latter being on the World Health Organization's blueprint list due to its high case-fatality rate and critical risk of emergence. Although an effective vaccine is available for MeV, this is not the case for NiV. Moreover, there is no cure for MeV- or NiV-infected patients that prevents the acute respiratory syndrome or lethal encephalitis. To identify new host factors to target for inhibiting viral growth, a library of metabolic modulators was screened for activity against MeV using an in vitro infection model. Results showed that Molidustat, a pharmacological inhibitor of Prolyl-Hydroxylase Domain (PHD) enzymes, inhibits MeV infection in a Hypoxia-Inducible Factor (HIF)-dependent manner. We then tested the antiviral effect of Molidustat in organotypic cultures of hamster cerebellum. Molidustat induced the hypoxia-response pathway in this ex vivo model as assessed by transcriptomic analysis, and inhibited MeV infection. A similar antiviral effect was observed with Roxadustat and Daprodustat, two PHD enzyme inhibitors chemically unrelated to Molidustat. Finally, we showed that Molidustat inhibits NiV infection in organotypic cultures of hamster cerebellum and lung, thereby validating its effect in the two organs mainly targeted during infection. Taken together, our results provide evidence that pharmacological activation of the hypoxia-response pathway restricts MeV and NiV infections, highlighting HIF-inducing drugs as promising candidates to consider in the development of treatments.

Keywords: Antiviral; Hypoxia-Inducible Factor; Measles virus; Molidustat; Nipah virus

DOI: https://doi.org/10.1080/22221751.2025.2563067

Front Mol Med. 2025 ;5 1599785

The role of aryl hydrocarbon receptor signalling in COVID-19 pathology and its therapeutic potential.

Saidon Mbambara, Ndimo Modipane, Thato Serite, Mike Sathekge, Mankgopo Kgatle.

Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, emerged in Wuhan, China, and rapidly evolved into a global health crisis. Recent evidence highlights the activation of the aryl hydrocarbon receptor (AHR) pathway following SARS-CoV-2 infection, implicating AHR in facilitating viral replication and impairing antiviral immunity. As a ligand-dependent transcription factor, AHR regulates immune responses, cellular differentiation, and proliferation, and is frequently exploited by viruses to evade host defences. In relation to COVID-19, AHR activation drives immune suppression, systemic inflammation, and metabolic disturbances, intensifying disease severity. Notably, in individuals with comorbidities such as obesity and diabetes, AHR overactivity exacerbates insulin resistance, oxidative stress, endothelial dysfunction, and thrombotic risk, contributing to cardiovascular complications. AHR also promotes airway remodelling and mucus hypersecretion, fostering respiratory dysfunction and fibrotic progression. This review synthesizes current insights into the mechanistic role of AHR signalling in SARS-CoV-2 pathogenesis and discusses its potential as a target for host-directed therapeutic interventions.

Keywords: COVID-19; SARS-CoV-2; aryl hydrocarbon receptor; comorbidities; diabetes; hypertension; inflammation; metabolic disorders

DOI: https://doi.org/10.3389/fmmed.2025.1599785