bims-mevinf 2025-12-14 papers

J Virol. 2025 Dec 09. e0164325

Bovine viral diarrhea virus suppresses type I IFN production by inducing MAVS degradation via autophagy mediated by the ROS-endoplasmic reticulum stress axis.

Jing Wang, Jiangfei Zhou, Yixin Wang, Wenlu Fan, Xinyue Xia, Jiarui Chen, Haiyue Zhu, Qianyao Wang, Xiao Li, Yimei Liu, Jiayi Xiang, Han Yu, Moxuan Mao, Renjie Xu, Jiacun Liu, Shuo Jia, Yuan Li, Yigang Xu.

Bovine viral diarrhea virus (BVDV) is a major animal pathogen with a broad host range, causing gastrointestinal, respiratory, and reproductive diseases in cattle worldwide. BVDV exists as two biotypes: cytopathic (cp) and non-cytopathic (ncp). Although both cpBVDV and ncpBVDV have developed sophisticated strategies to evade or subvert host antiviral innate immune response, the underlying mechanisms remain incompletely understood. Autophagy, a process essential for maintaining cellular homeostasis, plays an important role in regulating viral replication and antiviral immunity. In this study, we demonstrated that the induction of autophagy with rapamycin enhanced the production of infectious progeny for both cpBVDV and ncpBVDV, whereas pharmacological inhibition of autophagy with 3-MA reduced viral yields. We further showed that modulating autophagy significantly influenced the early stages of the viral life cycle and the production of type I IFN (IFN-I). Notably, overexpression of BECN1 suppressed the synthesis of IFN-α and IFN-β, thereby promoting the replication of both cpBVDV and ncpBVDV. Conversely, RNA interference-mediated knockdown of BECN1 potentiated the antiviral innate immune response and restricted viral replication. Mechanistically, BECN1 was found to inhibit RIG-I-MAVS pathway activation by promoting ubiquitination and subsequent degradation of mitochondrial antiviral signaling (MAVS) protein, leading to suppression of IFN-I production. Additionally, both cpBVDV and ncpBVDV were shown to induce autophagy via the ROS-endoplasmic reticulum stress axis. These findings deepen our understanding of how BVDV evades host immunity and may inform the development of preventive strategies against BVDV infection.
IMPORTANCE: Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea-mucosal disease, is a major global threat to cattle health. BVDV employs sophisticated strategies to evade host defense and facilitate its replication. Understanding these mechanisms is crucial for developing effective vaccines and antiviral agents. Our study elucidates how cytopathic BVDV and non-cytopathic BVDV subvert the host's antiviral innate immune response by exploiting autophagy to inhibit the RIG-I-MAVS pathway. A key finding is that BECN1-mediated autophagy directly targets MAVS protein for degradation via a specific BECN1 and MAVS interaction. Furthermore, we demonstrate that BVDV activates autophagy through ROS-ER stress axis to promote its replication. These insights reveal a novel immune evasion mechanism of BVDV and highlight the therapeutic potential of autophagy inhibition in treating BVDV-related diseases.

Keywords: ROS-ER stress-autophagy axis; bovine viral diarrhea virus (BVDV); mitochondrial antiviral signaling protein (MAVS); type I interferon

DOI: https://doi.org/10.1128/jvi.01643-25

J Virol. 2025 Dec 09. e0191725

Reactive oxygen species promotion drives auranofin's antiviral activity against hepatitis E virus.

Kateland Tiller, S Tyler Williams, Bo Wang, Debin Tian, Xiang-Jin Meng, James Weger-Lucarelli.

Hepatitis E virus (HEV) causes roughly 20 million yearly global infections and is associated with chronic hepatitis, neurological sequelae, and pregnancy-related adverse outcomes that require antiviral intervention. While there are no approved HEV-specific therapeutics, ribavirin and pegylated interferon, prescribed off-label, remain the current standard of care. However, ribavirin resistance and toxicity highlight the unmet clinical need to identify safer, HEV-specific antivirals. Here, we identify reactive oxygen species (ROS) promotion as a previously unrecognized host-directed antiviral mechanism against HEV, revealed through the activity of the FDA-approved drug auranofin. Auranofin, which is known to elevate intracellular ROS, displays antiviral activity against several viruses. We revealed here that auranofin exhibits robust, dose-dependent antiviral activity against two clinically relevant HEV genotypes and a ribavirin treatment failure-associated mutant. ROS inhibition reversed auranofin-mediated ROS promotion and antiviral activity, establishing a mechanistic link between ROS promotion and antiviral activity. Treatment with D-amino acid oxidase, which breaks down D-amino acids producing the ROS H2O2, exerted dose-dependent anti-HEV activity. This effect was reversed by ROS inhibition, demonstrating that ROS accumulation alone is sufficient for antiviral activity. We also revealed that ROS promotion by auranofin drives activation of antioxidant, ER stress, and interferon-stimulated gene expressions, further supporting induction of ROS-dependent antiviral signaling. Lastly, we demonstrated that combined treatment with auranofin and ribavirin exhibits synergistic antiviral activity in vitro. These findings highlight the promotion of ROS as a previously underappreciated host-directed antiviral mechanism and support the repurposing of auranofin-alone or in combination with ribavirin-as a therapeutic strategy against HEV.
IMPORTANCE: Hepatitis E virus (HEV) lacks approved virus-specific antiviral therapies, and off-label treatments with ribavirin and pegylated interferon are limited by toxicity and emerging resistance mutants. This study identifies reactive oxygen species (ROS) promotion mediated by the FDA-approved drug auranofin and D-amino acid oxidase as an effective antiviral strategy against multiple genotypes of HEV, including two globally relevant human-associated genotypes and a ribavirin treatment failure-associated HEV mutant. The observed synergistic anti-HEV activity in vitro for combined treatment with both auranofin and ribavirin suggests a potential clinically effective combinational therapeutic approach. ROS promotion through auranofin or other means represents an underexplored antiviral strategy with potential for broad-spectrum activity against a range of viral diseases.

Keywords: antiviral; auranofin; drug repurposing; hepatitis E virus; reactive oxygen species

DOI: https://doi.org/10.1128/jvi.01917-25

iScience. 2025 Dec 19. 28(12): 114018

CD38 is a key mediator of NAD+ depletion in the brain of ZIKV-infected mice.

Georgia N Saraiva, Bruna G Sousa, Nicole M S Souza, Louise C Vitorino, Raquel C da Silva, Thiago S Bacelar, Matheus O Atella, Lorena O Fernandes-Siqueira, Isis Nem de Oliveira Souza, Eduardo Nunes Chini, Juliana Camacho-Pereira, Giselle F Passos, Andrea T Da Poian, Julianna D Zeidler.

Zika virus (ZIKV) infection is a major health concern, particularly during pregnancy, as it can lead to neurodevelopmental delays and congenital brain abnormalities, including microcephaly. Here, we investigated the mechanisms of NAD+ depletion in the brains of ZIKV-infected neonatal mice, a model that developmentally corresponds to third-trimester infection in humans. We observed a progressive decline in NAD+ levels, which became significant at later stages of infection (18-30 dpi). This decrease did not correlate with viral replication and early Parp10 or Parp12 induction, which increased alongside Nampt expression, possibly as a compensatory response to NAD+ consumption. Instead, NAD+ depletion coincided with increased CD38 expression and activity, while CD38 inhibition prevented NAD+ loss. Late-stage NAD+ depletion was preceded by an induction of inflammatory markers (Il-6, Tnf, and Ccl5/Rantes) and coincided with the infiltration of CD38+ immune cells - especially lymphocytes - into the brain, suggesting a link between neuroinflammation and NAD+ metabolism dysregulation.

Keywords: Immunology; Neuroscience; Virology

DOI: https://doi.org/10.1016/j.isci.2025.114018

Microbiol Spectr. 2025 Dec 11. e0245625

D-glucose uptake inhibits bovine alphaherpesvirus 1 post-binding cell process entry via inhibition of PLC-γ1 signaling in a glucose transporter 1-independent manner.

Xuan Li, Xiuyan Ding, Naifan Zhang, Xiaozhen Ma, Filomena Fiorito, Liqian Zhu.

Bovine alphaherpesvirus 1 (BoAHV-1) is one of the most important viral pathogens responsible for severe economic losses in the cattle industry worldwide. We have previously shown that both phospholipase C gamma1 (PLC-γ1) and β-catenin signaling pathways play crucial roles in BoAHV-1 productive infection. In this study, we demonstrated that BoAHV-1 productive infection in bovine kidney (MDBK) cells and in bovine trigeminal ganglia neurons led to alteration of the protein expression and/or its subcellular localization glucose transporter 1 (GLUT1). In turn, GLUT1 signaling appeared to promote virus productive infection, partially by activating β-catenin-dependent transcriptional activity, as determined using GLUT1-specific small interfering RNAs or the GLUT1-specific inhibitor, BAY-876. Interestingly, D-glucose inhibited the virus post-binding cell entry process, partially through blocking PLC-γ1 signaling. Although GLUT1 is a key glucose transporter, the inhibitory effects of D-glucose on viral entry were independent of GLUT1. Moreover, we showed that D-glucose and the PLC-γ1-specific inhibitor U73122 synergistically inhibited virus cell entry. Collectively, for the first time, we revealed that D-glucose and its potential transporter GLUT1 had opposite effects on BoAHV-1 productive infection (inhibition vs promotion) via manipulation of different cell signaling pathways (PLC-γ1 vs β-catenin). These findings provide novel insights into the mechanisms underlying BoAHV-1 infection involving GLUT1 and glucose and highlight potential therapeutic targets for the development of antiviral strategies.
IMPORTANCE: Virus entry is a complex process that involves the binding of viral glycoproteins to host cell receptors, and various host factors can influence this process. Here, for the first time, we found that D-glucose has the potential to block bovine alphaherpesvirus 1 (BoAHV-1) post-binding cell entry process, possibly through the inactivation of PLC-γ1 signaling. Interestingly, D-glucose regulated PLC-γ1 signaling with a GLUT1-independent mechanism, though D-glucose uptake was partially mediated by GLUT1. We also identified that β-catenin acts as a potential downstream target of GLUT1, which may represent a mechanism regarding how GLUT1 signaling contributes to BoAHV-1 productive infection. Moreover, a distinct GLUT1 staining in the pre-nuclear regions, likely corresponding to the nuclear membrane, was exclusively observed in trigeminal ganglia neurons of latently infected calves, indicating that it is also potentially involved in the virus latency, which deserves further clarification in future studies.

Keywords: A549; Bovine alphaherpesvirus 1; GLUT1; MDBK; Neuro-2A; PLC-γ1; TG

DOI: https://doi.org/10.1128/spectrum.02456-25

Front Microbiol. 2025 ;16 1675667

CVB3-induced P62 cleavage promotes ferroptosis through the NRF2/GPX4 axis and facilitates viral replication.

Feng He, Zhuo Liu, Miao Feng, Dingding Cao, Sen Li, Xuelai Liu, Yiting Jiang, Xiaoyu Yi, Zhewei Liu, Hailan Yao.

Introduction: Coxsackievirus B3 (CVB3) represents a major etiological agent of viral myocarditis, whose propagation within host organs results in substantial tissue injury. The molecular pathways through which CVB3 exerts its pathological effects, particularly its connection to ferroptosis-a regulated cell death modality characterized by iron-dependent lipid peroxidation-remain incompletely defined.
Methods: We employed a combination of in vitro and in vivo models of CVB3 infection. Molecular techniques including immunoblotting, gene manipulation, and viral assays were used to investigate the proteolytic processing of the selective autophagy receptor P62 and its functional consequences. The role of the KEAP1/NRF2/GPX4 axis was examined using a non-cleavable P62 mutant. Furthermore, the therapeutic potential of a selenium-rich diet was evaluated in infected mice.
Results: Our data showed that CVB3 replication induces the cleavage of P62 into distinct C- and N-terminal fragments. This event promotes the degradation of the transcription factor NRF2, leading to the downregulation of its target, GPX4, a key inhibitor of ferroptosis. Expression of a non-cleavable P62 mutant effectively stabilized the KEAP1/NRF2/GPX4 pathway and attenuated ferroptotic cell death in both cellular and mice models. Notably, GPX4 levels were not modulated by ubiquitination during infection. Supplementation with a selenium-rich diet, crucial for GPX4 synthesis, suppressed ferroptosis and improved survival rates in CVB3-infected mice.
Discussion: This study identifies a novel mechanism whereby CVB3 exploits the cleavage of P62 to inactivate the KEAP1/NRF2/GPX4 axis, thereby driving ferroptosis and disease progression. These findings highlight the therapeutic potential of restoring P62 function and supplementing selenium to alleviate CVB3-induced pathogenesis.

Keywords: CVB3; GPx4; P62; ferroptosis; selenium; viral replication

DOI: https://doi.org/10.3389/fmicb.2025.1675667