bims-mevinf 2025-10-12 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–10–12
seven papers selected by
Alexander V. Ivanov, Engelhardt Institute of Molecular Biology

Ciclopirox suppresses poxvirus replication by targeting iron metabolism.
Integrated transcriptomic and metabolomic analysis identifies host response mechanisms to oncogenic Marek's disease virus in Wenchang chickens.
Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification.
pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity.
The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex.
Cholesterol in viral envelope determines infectivity of SARS-CoV-2 and other coronaviruses.
Reoviruses hijack the SMARCB1-MYC transcriptional regulation complex to activate autophagy for persistent viral infection in leafhopper vector.

Antiviral Res. 2025 Oct 07. pii: S0166-3542(25)00216-5. [Epub ahead of print] 106290

Ciclopirox suppresses poxvirus replication by targeting iron metabolism.

Anil Pant, Djamal Brahim Belhaouari, Lara Dsouza, D M Nirosh Udayanga, Zhengqiang Wang, Zhilong Yang.

  Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC50 in the sub-micromolar range and a CC50 >500 μM. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe3+ and, to a lesser extent, Fe2+, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment suppressed cowpox virus and monkeypox (mpox) virus replication in vitro. It also reduced VACV titers in ex vivo mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and identify CPX as a promising antiviral candidate against multiple orthopoxviruses.

Keywords:  Antiviral; Ciclopirox; Iron Metabolism; Monkeypox Virus; Mpox; Poxviruses

DOI:  https://doi.org/10.1016/j.antiviral.2025.106290
Vet Res. 2025 Oct 07. 56(1): 190

Integrated transcriptomic and metabolomic analysis identifies host response mechanisms to oncogenic Marek's disease virus in Wenchang chickens.

Xiangdong Xu, Junming Zhao, Sanchun He, Yuting Fang, Dan Liu, Tingbo Shen, Lifeng Zhi, Zheng Liu, Liguang Shi, Guanyu Hou, Runfeng Zhang, Guang Rong.

  Marek's disease (MD), caused by Marek's disease virus (MDV), poses a significant threat to the poultry industry worldwide by inducing neurological disorders and malignant lymphoma in infected chickens. The underlying mechanisms of the host response to MDV infection and tumorigenesis remain poorly understood. To gain insight into the host response, we analysed the transcriptomic and metabolomic profiles of the heart tissue of Wenchang chickens, an indigenous Chinese breed, using RNA sequencing and untargeted metabolomics. A total of 2470 and 2666 genes were significantly up- and down-regulated, respectively, between infected and uninfected chickens. KEGG pathway enrichment analysis revealed distinct transcriptional patterns in response to MDV infection: upregulated genes were enriched primarily in immunity-related pathways, whereas downregulated genes were associated with metabolic pathways. Among the 433 differentially expressed metabolites identified, only the caffeine metabolism pathway approached statistical significance (p = 0.067). Integrative mapping of genes and metabolites to the KEGG enzyme database highlighted L-tryptophan interactions, with KYNU, KMO, KYAT3, and AADAT as the most representative relationships. These results provide a quantitative overview of MDV-induced transcriptional and metabolic perturbations, suggesting that hosts may counteract viral infection and tumor progression by suppressing cellular metabolism to potentiate immune responses.

Keywords:  Marek’s disease; chicken; host response; metabolomics; transcriptomics

DOI:  https://doi.org/10.1186/s13567-025-01618-5
Emerg Microbes Infect. 2025 Dec;14(1): 2563079

Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification.

Zhiqiang Wei, Yanying Yan, Lingzhu Zhao, Chen Li, Jinjin Qi, Dandan Chen, Xiuzhen Huang, Minwei Li, Zhengyun Xiao, Guohua Lou, Zhenggang Yang, Mengji Lu, Xueyu Wang, Min Zheng.

  Mitochondria are vital for maintaining cellular homeostasis. However, mitochondrial damage is evident in patients with chronic hepatitis B (CHB). The role of mitochondrial dysfunction in the persistence of viral replication remains unclear. Therefore, this study aims to investigate the impact of mitochondrial dysfunction on HBV replication and elucidate the underlying mechanisms. Both mitochondria and lysosomes were dysfunctional in HBV-replicating cells. Moreover, HBV replication inhibited mitochondrial respiratory chain both in vitro and in vivo. Moderate inhibition of mitochondrial respiratory complex I activity using rotenone (Rot) increased HBV replication and decreased autophagic degradation capacity in vitro and in vivo. Mechanistically, elevated mitochondrial reactive oxygen species (mtROS) levels by Rot treatment or SOD2 knockdown led to deteriorated lysosomal membrane permeabilization, which elevated lysosomal pH and promoted HBV replication. Conversely, scavenging mtROS with mitoquinone (mitoQ) and mitoTEMPO (mitoT) had the opposite effect. Additionally, mitochondrial dysfunction reduced mitochondrial ATP production and diminished mitochondria-lysosome contacts. Obstructing mitochondrial ATP synthesis with Oligomycin A treatment or disruption of mitochondria-lysosome contacts with vacuolar protein sorting 13 A (VPS13A) knockdown resulted in lysosomal alkalinization and increased HBV replication by inhibiting vacuolar (H+)-adenosine triphosphatase (v-ATPase) assembly in an mtROS-independent manner. Ultimately, inhibition of mitochondrial complex I facilitated HBV secretion by promoting endosomal trafficking of HBV components. In conclusion, mitochondrial function plays a crucial role in HBV autophagic degradation. HBV impairs mitochondrial function, leading to a reduction in the lysosomal degradation capacity, which may hinder effective clearance of the virus.

Keywords:  Lysosomal degradation; V-ATPase assembly; hepatitis B virus; lysosomal membrane permeabilization; mitochondira-lysosomal contacts; mitochondrial ATP synthesis; mtROS

DOI:  https://doi.org/10.1080/22221751.2025.2563079
Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01177-5. [Epub ahead of print]44(10): 116406

pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity.

Ling-Dong Xu, Fei Zhang, Can Miao, Xinyuan Yu, Yezhang Zhu, Meng-Di Zhang, Shengduo Liu, Siddharth Sridhar, Qiming Sun, Dante Neculai, Qi Zhang, Li Shen, Tingbo Liang, Cunqi Ye, Yao-Wei Huang, Pinglong Xu.

  Lipid droplets (LDs) are dynamic organelles that mediate lipid metabolism and various cellular processes. However, the interplay between hepatocyte LDs and hepatitis E remains poorly understood. Using targeted lipidomics and lipid profiling in rodent models, we reveal that hepatitis E virus (HEV) infection substantially increases hepatic LD biogenesis. Mechanistically, HEV pORF3 is a key LD biogenesis inducer and an essential factor for viral infectivity in vivo. pORF3 undergoes liquid-liquid phase-separation to form condensates that associate with LD phospholipid monolayer peripherally to upregulate cholesterol anabolic pathways, thereby promoting triacylglycerol and cholesterol ester synthesis. Consistently, genetic loss of ORF3 or pharmacologic reduction of LD biogenesis with the statin atorvastatin substantially suppressed HEV infection in vivo. These findings identify LD biogenesis as a host dependency for HEV infectivity and propose alternative strategies for HEV intervention by targeting LD-directed metabolic pathways.

Keywords:  CP: Cell biology; CP: Microbiology; ORF3; antiviral treatment; atorvastatin; glucose metabolism; hepatitis E virus; lipid biogenesis; lipid droplet; liquid-liquid phase separation

DOI:  https://doi.org/10.1016/j.celrep.2025.116406
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2511857122

The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex.

Qiyu Wang, Lingyue Chen, Jiayin Wang, Zhijian Chen, Zixian Ma, Xuan Xie, Xiaohui Zeng, Yuanyuan Bie, Zhaowei Wang.

  The small interfering RNA (siRNA) pathway is a highly conserved antiviral defense mechanism in vertebrates and invertebrates. Although the core components of this pathway are well characterized, its upstream regulatory networks remain poorly understood. Here, we identify the integrated stress response (ISR) as a negative regulator of the siRNA pathway, and demonstrate that the picorna-like virus CrPV (Cricket Paralysis Virus) exploits this mechanism for immune evasion. Mechanistically, the picorna-like virus triggers the ISR through transcriptional suppression of ppp1r15, a key regulator of eukaryotic initiation factor 2α (eIF2α) dephosphorylation. ISR activation subsequently induces the autophagy-lysosomal pathway by up-regulating Atg1 transcription in an ATF4-dependent manner. This process leads to selective degradation of Argonaute 2 (Ago2) and other core components of the RNA-induced silencing complex (RISC), thereby suppressing the host RNA interference (RNAi) machinery and enhancing viral replication. Our findings uncover an unconventional immune evasion strategy employed by a picorna-like virus and establish a previously unrecognized crosstalk between the ISR and siRNA pathways.

Keywords:  RNA interference; autophagy; integrated stress response; picorna-like virus

DOI:  https://doi.org/10.1073/pnas.2511857122
Front Microbiol. 2025 ;16 1670356

Cholesterol in viral envelope determines infectivity of SARS-CoV-2 and other coronaviruses.

Xiaoying Xu, Xueyan Wang, Xiafeng Zhang, Xin Jin, Yun Tan, Lin Huang, Mingqian Zhou, Chengping Wen.

  The SARS-CoV-2 pandemic had unprecedented impacts on public health and the economy. Many studies have focused on the mechanisms of SARS-CoV-2 entry into host cells, particularly the spike (S) protein mediated receptor engagement and subsequent virus-host membrane fusion dynamics. However, the mechanistic contribution of cholesterol within spike-incorporated viral envelopes to infectivity has not been well characterized. Herein, we show that targeted cholesterol depletion from the viral envelopes of SARS-CoV-2, SARS-CoV, and MERS-CoV directly impaired viral infectivity in a dose-dependent manner. Although modulation of host cell membrane cholesterol exerted relatively minor effects on viral entry, host cellular cholesterol homeostasis critically governs progeny virion infectivity by determining cholesterol content within nascent viral envelopes. Virions derived from cells with reduced plasma membrane cholesterol demonstrate significantly attenuated infectivity in SARS-CoV-2 and related coronaviruses. In addition, we detected that exogenous cholesterol replenishment restored SARS-CoV-2 entry efficiency by augmenting virus attachment. Collectively, our data demonstrate that biophysical properties of human coronavirus envelopes, particularly cholesterol stoichiometry, function as a key molecular determinant regulating host cell susceptibility. These findings position viral lipidome remodeling as a viable therapeutic target for developing host-directed broad-spectrum antivirals.

Keywords:  entry efficiency; human coronaviruses; therapeutic target; viral attachment; viral envelope cholesterol

DOI:  https://doi.org/10.3389/fmicb.2025.1670356
PLoS Pathog. 2025 Oct;21(10): e1013569

Reoviruses hijack the SMARCB1-MYC transcriptional regulation complex to activate autophagy for persistent viral infection in leafhopper vector.

Hui Wang, Runfa Liu, Guangming Xiao, Yanan Li, Bozhong Li, Qian Chen, Taiyun Wei.

Autophagy plays a crucial role in virus-host interactions, as viral components and particles can be degraded by the host's autophagic machinery. Additionally, some viruses can hijack autophagy for their own benefit. However, the mechanisms underlying the transcriptional regulation of autophagy by arboviruses in insect vectors remain largely unexplored. In this study, we found that rice dwarf virus (RDV) infection activates the autophagy pathway in the leafhopper vector, Nephotettix cincticeps, and this autophagy activation also facilitates viral infection in the leafhopper. We identified that MYC transcription factor regulates the expression of autophagy proteins ATG5 and ATG8 by directly targeting their promoters. A transcription regulator SMARCB1 binds to MYC and impedes its recognition of the ATG5 and ATG8 promoters, thus negatively regulating their expression. Moreover, NcSMARCB1 negatively regulates ATG5 expression by directly binding to its promoter. RDV major outer capsid protein P8 blocks the nuclear translocation of SMARCB1, disrupting the SMARCB1-MYC interaction and thereby relieving the transcriptional inhibition of ATG5 and ATG8, which leads to autophagy activation. Furthermore, major outer capsid protein P8 of rice gall dwarf virus (RGDV), same to RDV belonging to plant reoviruses, also interacts with SMARCB1 in leafhopper Recilia dorsalis, preventing its nuclear translocation. Similarly, suppression of SMARCB1 expression enhances autophagy formation and promotes RGDV infection. These findings highlight the critical role of insect vector SMARCB1 and MYC in regulating autophagy in response to arbovirus infection.

DOI: https://doi.org/10.1371/journal.ppat.1013569