bims-mevinf 2025-09-14 papers

Front Microbiol. 2025 ;16 1658838

The role of glycerophospholipid metabolism in feline parvovirus infected CRFK cells.

Zhen Sun, Hongwei Zhu, Yang Liu, Jianlong Zhang, Linlin Jiang, Xin Yu, Jiayu Yu, Xingxiao Zhang.

Background: Feline panleukopenia, caused by the highly lethal feline parvovirus (FPV), lacks effective prevention and treatment strategies. This study aimed to elucidate the key metabolic regulatory mechanisms during FPV infection.
Methods: CRFK cells were infected with the FPV013 strain. Viral identification was performed via cytopathic effect (CPE) observation, transmission electron microscopy (TEM), PCR, and VP2 protein detection using Western blot and immunofluorescence. Untargeted metabolomics analyzed metabolic changes at 12 h, 24 h, and 48 h post-infection (hpi). Key pathways were validated through enzyme activity inhibition (Meclizine targeting PCYT2) and gene silencing (siRNA targeting PLPP1 and LPIN3).
Results: Metabolomics revealed the most significant differences at 48 hpi, identifying six significantly altered glycerophospholipid metabolites. Inhibiting PCYT2 enzyme activity significantly reduced viral load (p < 0.01). Silencing either phospholipid phosphatase 1 (PLPP1) or LPIN3 significantly inhibited FPV replication, with IF staining showing reduced VP2 expression (p < 0.01). In contrast, blocking fatty acid synthesis (TOFA/C75 treatment) had no significant effect.
Conclusion: FPV infection promotes replication by reprogramming host cell glycerophospholipid metabolism. The PCYT2-mediated PE/PC synthesis pathway and the PLPP1 or LPIN3 regulated diacylglycerol (DG) generation pathway play central roles. This finding highlights the pivotal role of glycerophospholipid metabolism during FPV infection, offering insights into antiviral strategies targeting this pathway.

Keywords: FPV013; Lpin3; PLPP1; glycerophospholipid metabolism; viral replication

DOI: https://doi.org/10.3389/fmicb.2025.1658838

Tissue Cell. 2025 Sep 09. pii: S0040-8166(25)00416-1. [Epub ahead of print]98 103134

Intracellullar cholesterol accumulation caused by HBV induces ATF6-mediated endoplasmic reticulum stress to trigger endoplasmic reticulophagy.

Yongxu Lin, Pingying Jiang, Weiqi Cai, Yongzhu Huang, Qiuyan Lin, Mingrong Wang, Fenglin Chen, Yuanlin Qi, Dan Li.

BACKGROUD: Hepatitis B virus (HBV) infection can cause cholesterol accumulation, induce endoplasmic reticulum stress (ERS) and enhance autophagy in hepatocytes. However, the mechanisms underlying these interactions remain unclear, as well as the potential benefit of cholesterol-lowering treatment in patients with chronic hepatitis B (CHB). Therefore, the effects of of cholesterol accumulation caused by HBV on ERS and autophagy were explored in this study, aiming to identify the key molecules mediating the crosstalk between ERS and endoplasmic reticulophagy (ER-phagy).
METHODS: Bioinformatics, immunohistochemistry (IHC), proteomics, western blot, and transmission electron microscopy (TEM) were used to analyse clinical specimens, HBV transgenic animal and cell models.
RESULTS: Analysis of Gene Expression Omnibus (GEO) database demonstrated that the transcription levels of LDLR, SREBF2/SREBP2, ATF6, MAP1LC3B/LC3B and SQSTM1/P62 in CHB tissues were higher than those in normal liver tissues. The IHC results showed that the expressions of LDLR, SREBP2, GRP78, ATF6, LC3B, P62 and FAM134B in CHB tissues were higher than those in normal liver tissues. The free cholesterol content, the expression of GRP78, ATF6, LC3B II, P62 and FAM134B were higher in the livers of HBV transgenic mice and HepG2.2.15 cells compared with their control groups. TEM showed endoplasmic reticulum (ER) expansion and degranulation, as well as ER-phagy, in the livers of HBV transgenic mice and HepG2.2.15 cells. Furthermore, melatonin administration, an ATF6 inhibitor, attenuated hepatic inflammation, alleviated ERS, downregulated ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells. Fatostatin administration, a cholesterol synthesis inhibitor, attenuated hepatic inflammation, decreased the free cholesterol content, alleviated ERS, downregulated GRP78 and ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells CONCLUSION: HBV infection leads to cholesterol accumulation in hepatocytes, which promotes ATF6-mediated ERS and FAM134B-mediated ER-phagy. Reducing intracellular cholesterol accumulation alleviates ATF6-mediated ERS, inhibits FAM134B-mediated ER-phagy, and attenuates hepatic inflammation. ATF6 may represent a promising therapeutic target for an adjuvant treatment of CHB. Our study provides experimental evidence for the use of statin as an adjuvant treatment of CHB.

Keywords: Activating transcription factor 6; Cholesterol metabolism; Endoplasmic reticulophagy; Endoplasmic reticulum stress; Hepatitis B virus

DOI: https://doi.org/10.1016/j.tice.2025.103134

J Virol. 2025 Sep 10. e0132325

The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication.

Stuart Weston, Lauren Baracco, Louis Taylor, Alison J Scott, Gaurav Kumar, Paul Shapiro, Alexander D MacKerell, Matthew B Frieman.

There is a need for the development of broad-spectrum antiviral compounds that can act as first-line therapeutic countermeasures to emerging viral infections. Host-directed approaches present a promising avenue of development and carry the benefit of mitigating risks of viral escape mutants. We have previously found the SKI (super killer) complex to be a broad-spectrum, host-target with our lead compound ("UMB18") showing activity against influenza A virus, coronaviruses, and filoviruses. The SKI complex is a cytosolic RNA helicase, and we previously found that UMB18 inhibited viral RNA production but did not further define the mechanism. Here, we demonstrate that UMB18 directly binds to SKIC8 of the SKI complex, and transcriptomic analysis of UMB18-treated A549 cells revealed an upregulation of genes in the mevalonate pathway, which drives cholesterol synthesis. Further investigation validated the genetic upregulation and confirmed an increase in total cellular cholesterol. This upregulation was dependent on the sterol regulatory element-binding proteins (SREBPs) and their regulator SCAP, the major regulators for cholesterol and fatty acid synthesis. Depletion of the SREBPs or SCAP with siRNA, or extraction of cholesterol with methyl β-cyclodextrin, attenuated UMB18 antiviral activity, emphasizing the role of increased cholesterol synthesis in this mechanism of action. Our findings further define the antiviral mechanism of a developmental host-directed therapeutic approach with broad applicability against emerging viral pathogens.
IMPORTANCE: The COVID-19 pandemic has underscored the need for effective countermeasures to emerging pathogens. Our research builds upon our published data on a novel antiviral compound termed UMB18. We have found UMB18 capable of inhibiting replication of influenza A virus, coronaviruses, and the filoviruses Marburg and Ebola virus, but did not fully define a mechanism of action. Here, we demonstrate that UMB18 exerts antiviral activity by modulating cellular cholesterol levels. By targeting the SKI complex, UMB18 triggers an increase in endogenous cellular cholesterol, which disrupts the fine balance that viruses rely on for efficient infection. We demonstrate that this mechanism inhibits replication of SARS-CoV-2, revealing a previously undescribed host-directed strategy for antiviral intervention. These findings highlight UMB18's potential as a broad-spectrum antiviral agent and pave the way for further research into its mechanism and therapeutic applications, offering a promising avenue for development of antiviral countermeasures to current, novel, and emerging pathogens.

Keywords: antiviral; cholesterol; coronavirus

DOI: https://doi.org/10.1128/jvi.01323-25

Microb Pathog. 2025 Sep 08. pii: S0882-4010(25)00748-X. [Epub ahead of print] 108023

ACE2 Mitigates PEDV-induced Endoplasmic Reticulum Stress and Autophagy by Inhibiting ROS Production.

Zhiqiang Li, Xueqing Chen, Chang Ma, Gongmin Wang, Yuanshu Zhang.

Role of ACE2 in regulating inflammatory damage has been recognized, its association with ER stress and autophagy under PEDV infection remains elusive. To clarify the above associations, this study first established a stress injury model through PEDV infection to determine whether it can induce ER stress or autophagy. Then, the relationships between ER stress, autophagy and ROS under PEDV infection were verified. Finally, the immune regulatory role and molecular mechanism of ACE2 in PEDV induced ER stress and autophagy were explored by regulating the expression of ACE2. The results showed that PEDV elicited ER stress and activates the UPR response. Autophagy was triggered by PEDV to facilitate its replication with the involvement of ER stress as a mediator. ER stress and autophagy were both consequences of PEDV replication within cells. PEDV caused accumulation of ROS. ROS plays a pivotal role as an upstream regulatory factor in ER stress and autophagy. However, ACE2 plays a pivotal regulatory role in the aforementioned cellular processes. ACE2 inhibited ER stress and autophagy by reducing intracellular ROS production. These results reveal that PEDV infection can induce ER stress and mediate the occurrence of autophagy, and this process is regulated by the upstream factor ROS. Overexpression of ACE2 inhibits ER stress and autophagy by reducing the production of intracellular ROS, thereby restoring the REDOX homeostasis of host cells, and mitigating cell damage caused by PEDV. The research results provide new ideas and theoretical basis for ACE2 in intestinal inflammatory injury induced by PEDV infection.

Keywords: ACE2; Autophagy; Endoplasmic reticulum stress; PEDV; ROS