bims-mevinf 2025-01-26 papers

Cell Biosci. 2025 Jan 22. 15(1): 6

Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis.

Mengyuan Li, Hang Yuan, Xiaofei Yang, Yingfeng Lei, Jianqi Lian.

BACKGROUND: Japanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies.
METHODS: Metabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice.
RESULTS: Here, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice.
CONCLUSION: Altogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.

Keywords: Japanese encephalitis virus; Metabolism; Viral encephalitis

DOI: https://doi.org/10.1186/s13578-024-01340-3

EMBO Mol Med. 2025 Jan 22.

FABP4 as a therapeutic host target controlling SARS-CoV-2 infection.

Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV-2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.

Keywords: COVID-19; FABP4; Lipid Droplets; Replication Organelles; SARS-CoV-2

DOI: https://doi.org/10.1038/s44321-024-00188-x

Dev Comp Immunol. 2025 Jan 21. pii: S0145-305X(25)00013-8. [Epub ahead of print] 105324

Oridonin inhibits SGIV infection by regulating glycolipid metabolism and inflammatory response.

Yunxiang Jiang, Leshan Ruan, Jiatao Chen, Qiwei Qin, Shina Wei.

Singapore grouper iridovirus (SGIV) is a significant infectious disease in the grouper aquaculture industry. Currently, there is no effective drug available to prevent or treat SGIV. Oridonin (Ori) is a naturally occurring compound derived from Rabdosia rubescens, exhibiting various biological activities, including anti-tumor, anti-inflammatory, and antioxidant properties. In this study, we examined the anti-SGIV activity of Ori and its potential mechanism of action in vitro. The study results indicate that Ori effectively inhibits SGIV infection at various concentrations. Further studies reveal that Ori inhibits the formation of lipid droplets induced by SGIV infection. Additionally, Ori suppresses the SGIV-induced up-regulation of fatty acid synthesis-related genes (SREBP1, ACC1, SCD1, FASN) and glycolysis-related genes (GLUT1, GLUT2, HK2, PDHX). The mTOR pathway plays a crucial role in regulating glycolipid metabolism. Our findings indicate that Ori suppresses the phosphorylation of AKT and mTOR proteins. Further research revealed that the activation or inhibition of mTOR significantly impacts SGIV protein production and the expression of genes related to glycolipid metabolism. In addition, Ori effectively inhibits the up-regulation of NLRP3, ASC, Caspase-1, and pro-inflammatory cytokines induced by SGIV infection. In conclusion, our experimental findings indicate that Ori effectively inhibits SGIV infection by regulating glycolipid metabolism through the AKT/mTOR pathway and by suppressing the inflammatory responses triggered by SGIV infection.

Keywords: Glucolipid Metabolism; Inflammation; Lipid Droplets; Oridonin; SGIV

DOI: https://doi.org/10.1016/j.dci.2025.105324

iScience. 2025 Jan 17. 28(1): 111599

Dengue virus and Zika virus alter endoplasmic reticulum-mitochondria contact sites to regulate respiration and apoptosis.

During infection, dengue virus (DENV) and Zika virus (ZIKV), two (ortho)flaviviruses of public health concern worldwide, induce alterations of mitochondria morphology to favor viral replication, suggesting a viral co-opting of mitochondria functions. Here, we performed an extensive transmission electron microscopy-based quantitative analysis to demonstrate that both DENV and ZIKV alter endoplasmic reticulum-mitochondria contact sites (ERMC). This correlated at the molecular level with an impairment of ERMC tethering protein complexes located at the surface of both organelles. Furthermore, virus infection modulated the mitochondrial oxygen consumption rate. Consistently, metabolomic and mitoproteomic analyses revealed a decrease in the abundance of several metabolites of the Krebs cycle and changes in the stoichiometry of the electron transport chain. Most importantly, ERMC destabilization by protein knockdown increased virus replication while dampening ZIKV-induced apoptosis. Overall, our results support the notion that flaviviruses hijack ERMCs to generate a cytoplasmic environment beneficial for sustained and efficient replication.

Keywords: Cell biology; Membranes; Metabolomics; Proteomics; Virology

DOI: https://doi.org/10.1016/j.isci.2024.111599

BMC Ophthalmol. 2025 Jan 23. 25(1): 43

Tear metabolomics reveals novel potential biomarkers in epithelial herpes simplex keratitis.

Jinyu Zhang, Zhenning Wu, Yangqi Zhang, Kaili Wu, Xiaoyi Li, Shiyou Zhou.

BACKGROUND: Herpes simplex keratitis (HSK) is a recurrent inflammatory disease of cornea primarily initiated by type I herpes simplex virus infection of corneal epithelium. However, early diagnosis of HSK remains challenging due to the lack of specific biomarkers. This study aims to identify biomarkers for HSK through tear metabolomics analysis between HSK and healthy individuals.
METHODS: We conducted a cross-sectional study enrolling 33 participants. Tear samples were collected from one eye of 18 HSK patients and 15 healthy volunteers using Schirmer-strips. Tear metabolomic profiling was performed using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Metabolites were quantified and matched against entries in the human metabolome database (HMDB) and small molecule pathway database (SMPDB) to identify metabolites and metabolic pathways, respectively. Metabolic differences between HSK and control group were determined using multivariate statistical analysis.
RESULTS: A total of 329 metabolites were identified, of which 18 were significantly altered in HSK patients. Notably, 12 metabolites were significantly increased, and 6 were significantly decreased in HSK patients. The changed metabolites were enriched in these pathways: arginine and proline metabolism, phospholipid biosynthesis, alpha linolenic acid and linoleic acid metabolism, retinol metabolism. To assess the potential utility of tear biomarkers, a predictive model was developed combining 4 metabolites (AUC = 0.998 [95%CI: 0.975, 1]): D-proline, linoelaidic acid, plantagonine, and phosphorylcholine.
CONCLUSIONS: Our study establishes that HSK has a distinctive metabolomic profile, with 4 key elements maybe emerging as potential biomarkers for diagnostic purposes. These findings may provide novel insights into early and rapid diagnosis of HSK.

Keywords: Herpes simplex keratitis; Metabolomics; Tear metabolites

DOI: https://doi.org/10.1186/s12886-025-03875-6

bioRxiv. 2025 Jan 09. pii: 2025.01.08.632057. [Epub ahead of print]

SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway.

Hua Yang, Pak-Hin Hinson Cheung, Li Wu.

Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis in cells, but its effects on HIV-1-induced apoptosis and the underlying mechanisms remain unknown. Here we uncover a new mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. We found that endogenous SAMHD1 enhances apoptosis levels induced by HIV-1 infection in dividing THP-1 cells. Mechanistically, SAMHD1 expression decreases the mitochondrial membrane potential and promotes cytochrome c release induced by HIV-1 infection in THP-1 cells, thereby enhancing mitochondrial apoptotic pathway. SAMHD1-enhanced apoptosis is associated with increased expression of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells. We further demonstrated that BIK contributes to SAMHD1-enhanced apoptosis during HIV-1 infection. Overall, our results reveal an unappreciated regulatory mechanism of SAMHD1 in enhancing HIV-1-induced apoptosis via the mitochondrial pathway in monocytic cells.

Keywords: BCL-2-interacting killer; HIV-1 infection; SAMHD1; THP-1 cells; apoptosis; cytochrome c; mitochondrial membrane potential; mitochondrial pathway; monocytic cells

DOI: https://doi.org/10.1101/2025.01.08.632057