bims-mevinf 2025-07-27 papers

Vet Res. 2025 Jul 21. 56(1): 156

Increased ROS levels activate AMPK-ULK1-mediated mitophagy to promote pseudorabies virus replication.

Yuan Zhao, Xiaoyi Qi, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Xiangdong Li.

Increasing evidence has confirmed that oxidative stress plays a nonnegligible role in the viral pathogenic process. In this study, we investigated the role of reactive oxygen species (ROS) in the replication of pseudorabies virus (PRV). Our data showed that PRV infection initially enhanced the contact between the endoplasmic reticulum (ER) and mitochondria, leading to an upsurge of mitochondrial Ca2+ (mtCa2+) concentration, which resulted in the loss of mitochondrial membrane potential (MMP) and excessive ROS production. Instead of translocating it to the nucleus, PRV infection concurrently sequestered Nrf2 in cytoplasm impeding the efficient scavenging of intracellular ROS. The excessive ROS production and failure in ROS clearance contributed to the persistently high ROS levels during PRV infection. Furthermore, elevated ROS levels elicited activation of the AMPK-ULK1 axis, initiating PINK1-Parkin-dependent mitophagy that selectively degraded damaged mitochondria along with mitochondrial-localized mitochondrial antiviral signaling protein (MAVS). This process suppressed MAVS-mediated type I interferon responses by eliminating both dysfunctional mitochondria and their associated antiviral signaling platforms, thereby creating a cellular environment permissive to viral replication. Overall, our findings elucidated the mechanism by which ROS enables the virus to resist the host interferon immune response and provided a theoretical basis for ROS-based antiviral strategies.

Keywords: AMPK; Nrf2; Pseudorabies virus; mitochondria Ca2+ ; mitophagy; reactive oxygen species

DOI: https://doi.org/10.1186/s13567-025-01595-9

Antiviral Res. 2025 Jul 18. pii: S0166-3542(25)00165-2. [Epub ahead of print] 106239

Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by its architectural damage and blocking HN protein.

Satyendu Nandy, Siddharth Neog, Sachin Kumar.

Cholesterol 25-hydroxylase (CH25H) is a membrane-bound endoplasmic reticulum protein that converts cholesterol into 25-hydroxycholesterol (25HC). Recent studies showed that CH25H is an interferon-stimulated gene (ISG) that helps fight various viruses and has broad antiviral effects. However, the role of chicken CH25H (chCH25H) in controlling Newcastle disease virus (NDV) infection and replication remains unexplored. This study examined the impact of chCH25H on NDV infection in chicken embryo fibroblast cells. The results showed that cells try to upregulate the chCH25H expression temporally upon viral infection. Moreover, the overexpression of chCH25H reduced NDV infection in cells while reducing endogenous chCH25H levels increased its replication. Additionally, treating cells and viruses with 25HC, an active metabolic intermediate of chCH25H, significantly reduced NDV replication by blocking the virus from entering cells while causing significant structural damage to the virus architecture. In addition, in ovo results also exhibited that the eggs treated with lipopolysaccharides (LPS), a positive regulator of chCH25H and 25HC, resulted in extensive viral reduction. These findings indicate that chCH25H and 25HC are against NDV replication in chicken fibroblast cells.

Keywords: 25HC; CH25H; ISGs; NDV; Pathogenicity

DOI: https://doi.org/10.1016/j.antiviral.2025.106239

Virol J. 2025 Jul 23. 22(1): 251

Metabolic characteristics in orthoflaviviral infections: unveiling pathogenic mechanisms and therapeutic targets.

Zhiwei Su, Ningze Sun, Xiaoyan Zheng.

Infections caused by mosquito-borne viruses such as Dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV) have become a global public health issue. However, due to the unclear pathogenic mechanisms, there are currently no specific treatments available for patients infected with these orthoflaviviruses in clinical practice. Metabolomics provides distinct advantages for characterizing infection features and deciphering disease pathogenesis. Therefore, this review summarizes relevant literature on mosquito-borne viruses metabolomics, with a particular focus on elucidating the metabolic characteristics of cells infected by orthoflaviviruses. By conducting a comparative analysis of the metabolomics data from different sample sources infected with DENV, ZIKV, and JEV, we found that several metabolic pathways involved in viral infection, replication, and pathogenesis are commonly disrupted in the metabolomics data of these orthoflaviviruses. These pathways include the reprogramming of lipid metabolism, interference with energy metabolism, and the induction of host inflammatory responses. These findings identify key targets for subsequent mechanistic studies on the persistent replication and transmission of orthoflaviviruses in mosquito vectors and their ability to cause severe pathology in human hosts. Further elucidations of the above mechanisms could provide an effective scheme for preventing orthoflaviviral transmission in mosquito vectors and treating orthoflaviviral infections. In addition, studying these metabolomic changes in human hosts of orthoflaviviral infections may be able to provide relevant biomarkers for accurate diagnosis of the disease.

Keywords: Biomarkers; Metabolomics; Mosquito-borne viruses; Orthoflaviviruses

DOI: https://doi.org/10.1186/s12985-025-02888-3

J Lipid Res. 2025 Jul 21. pii: S0022-2275(25)00128-2. [Epub ahead of print] 100866

HBV-miR-3 induces hepatic cholesterol accumulation by targeting ABCA1: evidence for potential benefits of statin usage.

Shruti Chowdhari, Auroni Deep, Belal Ahmad, Jasmine Samal, Ekta Gupta, Perumal Vivekanandan.

The cellular targets of hepatitis B virus (HBV)-encoded miRNAs remain poorly understood. The evolutionary conservation of HBV-miR-3 across HBV genotypes suggests its potential functional importance. Transcriptome profiling of HBV-miR-3 expressing hepatocytes demonstrates differential expression of several genes associated with lipid metabolic processes. The cholesterol efflux regulator gene ABCA1 was found to be down-regulated in our microarray data and in GEO datasets from HBV infected liver. We validated ABCA1 as a bonafide target of HBV-miR-3. HBV-miR-3-mediated suppression of ABCA1 led to increased cholesterol and lipid droplet accumulation in addition to increased proliferation and colony formation in hepatocyte cell lines. Interestingly, widely prescribed cholesterol-lowering drugs (simvastatin, atorvastatin and fluvastatin) could inhibit pro-oncogenic effects of HBV-miR-3. HBV-miR-3 expression was detectable in all liver biopsies (n=20) from chronic HBV (CHBV) patients. Patients with high intrahepatic HBV loads had higher levels of HBV-miR-3, suggesting that the virus-encoded miRNA levels correlate with virus replication. Patients with high HBV-miR-3 expression had significantly lower ABCA1 transcript levels in the liver. Hepatic steatosis was more frequently observed in biopsies of patients with high intrahepatic HBV-miR-3 levels compared to those with low HBV-miR-3 levels (71% vs 53%), although this was not statistically significant. Taken together, our findings support the notion that HBV-miR-3-mediated suppression of ABCA1 contributes to dysregulation of lipid metabolism in CHBV infection. In sum, HBV-miR-3 may represent the 'missing link' between CHBV and altered lipid metabolism in hepatocytes. Statin-mediated inhibition of HBV-miR-3-induced intrahepatic lipid accumulation and cell proliferation has potential clinical utility and merits further investigation.

Keywords: ABCA1; HBV-miR-3; HCC; cholesterol; hepatic steatosis; hepatitis B virus

DOI: https://doi.org/10.1016/j.jlr.2025.100866

Cell Death Dis. 2025 Jul 18. 16(1): 534

IFN-β production promotes metabolic rewiring and protection against oxidative stress in hepatitis delta virus-infected hepatocyte cultures.

Olga A Khomich, Patrick Giavalisco, Romain Parent, George S Krasnov, Peter Tessarz, Philip Meuleman, Rani Burm, Natalia F Zakirova, Jennifer Molle, Enkhtuul Batbold, Eyal Gottlieb, Fabien Zoulim, Alexander V Ivanov, Birke Bartosch.

Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is - in contrast to HBV - a strong inducer of interferon responses, including IFN-β. As the role of IFN- β in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures. Transcriptome analysis, isotope tracing and functional tests on differentiated, HDV-infected hepatocytes showed reduction of mitochondrial TCA cycle and respiratory activity and increases in serine, asparagine and glutathione synthesis. Furthermore, the stress-response factor ATF4 was activated by IFN-β via yet unidentified non-canonical mechanisms and mediated resistance to oxidants. IFN-β furthermore reduced the expression and activity of liver differentiation markers. Thus, IFN-β-mediated dedifferentiation and stress-resistance may contribute to HDV-associated liver pathology.

DOI: https://doi.org/10.1038/s41419-025-07838-z