bims-mevinf 2026-01-04 papers

Vet Sci. 2025 Dec 10. pii: 1176. [Epub ahead of print]12(12):

Let-7f-5p Inhibits PRRSV Replication by Regulating Lipid Metabolic Reprogramming in Infected Cells.

Dongfeng Jiang, Jin Huang, Xiaotong Wang, Guangwei Zhao, Congcong Li, Liyu Yang, Xiangge Meng, Qiuliang Xu.

Lipids provide essential membrane components and energy sources for viral replication, playing multiple roles in viral infection. However, the mutual influence between lipid metabolism and PRRSV proliferation remains unclear. Using transcriptomics, lipidomics, BODIPY staining, and Western blot (WB) analysis, our findings revealed that PRRSV infection significantly altered the abundance of lipid-metabolism-associated genes and lipid metabolites in cells. qRT-PCR confirmed that PRRSV infection dose-dependently upregulated SREBP2 expression (p < 0.01), while BODIPY staining demonstrated a significant increase in intracellular lipid droplets post-infection (p < 0.01). Let-7f-5p significantly reduced lipid droplet accumulation and suppressed PRRSV N protein expression. Notably, 15 lipid species that were upregulated during PRRSV infection were downregulated by let-7f-5p overexpression. These lipids were enriched in pathways related to phosphatidylcholines, monounsaturated fatty acids, and C16-C18 fatty acid metabolism. Exogenous palmitic acid (C16:0) treatment reversed the inhibitory effects of let-7f-5p on SREBP2 expression and viral replication, demonstrating that viral proliferation can be regulated by modulating host lipid metabolism. This study reveals that PRRSV hijacks host lipid metabolism to facilitate viral replication, whereas let-7f-5p exerts antiviral effects through dual mechanisms. These findings provide new insights into host-directed antiviral strategies against PRRSV infection.

Keywords: PRRSV; SREBP2; let-7f-5p; lipid metabolism; pig

DOI: https://doi.org/10.3390/vetsci12121176

Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2419820122

Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection.

Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.

Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (TexSTEM), which generates TexINT that directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased TexSTEM and their mitochondrial potential. The last-mentioned treatment also led to reduced TexINT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control. Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.

Keywords: CD8 T cell exhaustion; fatty acids; metabolomics; stem-like cells; viral infection

DOI: https://doi.org/10.1073/pnas.2419820122

Pathogens. 2025 Dec 16. pii: 1292. [Epub ahead of print]14(12):

Interplay Between NLRP3 Activation by DENV-2 and Autophagy and Its Impact on Lipid Metabolism in HMEC-1 Cells.

Giovani Visoso-Carvajal, Julio García-Cordero, Yandy Ybalmea-Gómez, Margarita Diaz-Flores, Moisés León-Juárez, Rosaura Hernández-Rivas, Porfirio Nava, Nicolás Villegas-Sepúlveda, Leticia Cedillo-Barrón.

Dengue Virus (DENV) induces assembly of the NOD-like receptor (NLR) family pyrin domain containing-3 (NLRP3) inflammasome and autophagy, which are closely interconnected processes playing crucial roles in lipid metabolism and DENV replication. However, the autophagy-NLRP3 activation interplay during DENV infection in human endothelial cells remains incompletely understood. We aimed to elucidate effects of NLRP3 activation on autophagy during DENV-2 infection. We investigated how autophagy-related molecules are altered by NLRP3 inhibition and how this regulation affects lipid metabolism, through the master lipid transcription factors SREBP-1 and 2, which increase the expression of their target lipid-synthesizing genes such as fatty acid synthase (FAS) in a model of microvascular endothelial cells (HMEC-1). We demonstrated a dynamic interplay between inflammasome activity and autophagy in DENV-infected HMEC-1 cells: autophagy increases early during infection and decreases as inflammasome activity increases. NLRP3 inflammasome inhibition affects viral replication. Glyburide (an inflammasome inhibitor) treatment partially inhibited DENV-induced NLRP3 inflammasome activation. Non-structural viral protein expression (NS3 and NS5) and infectious viral-particle formation were significantly reduced. NLRP3 inhibition also downregulated SREBP-1 and SREBP-2 activation. These findings provide new insights into the modulation of the interconnected NLRP3 inflammasome, autophagy, and lipid metabolism pathways, presenting a promising therapeutic strategy for severe clinical forms of dengue.

Keywords: Beclin-1; LC3; NLRP3; SREBP-1; SREBP-2; fatty acid synthase; glyburide

DOI: https://doi.org/10.3390/pathogens14121292

Front Cell Infect Microbiol. 2025 ;15 1673229

Autophagic regulation of CD8+ T cell metabolic reprogramming defines acute and latent phases of cytomegalovirus infection in vivo.

Hui Liu, Xiaobing Liu, Wai Ho Oscar Yeung, Jiang Liu, Kevin Tak Pan Ng, Kwan Man.

Understanding the immunoregulatory mechanism during cytomegalovirus (CMV) infection may help to combat CMV reactivation in immunocompromised or immunosuppressed individuals. Here we developed a CMV infection model in immunocompetent Sprague Dawley (SD) rats with Priscott strain and explored the cross-talk between autophagic dynamics and metabolism alterations in CD8+ T cells post infection. We previously found that primary CMV infection induced a remarkable increase of CD8+ T cells which reached the peak around week 3 and returned to pre-inoculation status since week 6 post viral infection. In this study, our results demonstrated that the autophagic activity of CD8+ T cells was augmented at week 3 while decreased at week 6, which was closely associated with the up- (week 3 and 4) or down-regulation (since week 6) of metabolic markers ENTPD1 and SLC27A2. Furthermore, the in vitro study showed that the levels of these metabolic markers in rat splenocytes were modulated by autophagy inhibitors and enhancers. Our study indicated that the dynamic alterations of autophagy exerted a critical role in regulating the metabolic adaptation of CD8+ T cells during CMV infection process, and provides an ideal animal model for further research on the pathological mechanisms based on CMV latency.

Keywords: CD8+ T cells; autophagic dynamics; cytomegalovirus; metabolism; sprague-dawley rats

DOI: https://doi.org/10.3389/fcimb.2025.1673229

Autophagy. 2026 Jan 01. 1-19

Senecavirus a VP2 protein orchestrates PRDX1 degradation through dual autophagy pathways: macroautophagy and chaperone-mediated autophagy.

Zhaoyang Li, Xiaoyu Yang, Jingyu Mao, Penghui Zeng, Yuxiang Qi, Yongyan Shi, Jinshuo Guo, Jianwei Zhou, Dedong Wang, Jue Liu, Lei Hou.

Co-adaptation between viruses and autophagy has equipped viruses with diverse strategies to regulate host redox homeostasis, thereby facilitating viral replication. However, the mechanisms by which viruses manipulate PRDX1 (peroxiredoxin 1), a key antioxidative enzyme, via autophagy remain poorly understood. Here, we demonstrate that infection by Senecavirus A (SVA), an emerging picornavirus, induces PRDX1 degradation, and that PRDX1 negatively regulates viral replication. Decreased PRDX1 expression impairs cellular antioxidant defenses, leading to enhanced reactive oxygen species generation that facilitates SVA replication. Screening of viral proteins revealed that SVA VP1, VP2, and 3A induce PRDX1 degradation through vesicle formation-dependent macroautophagy. Notably, viral VP2 can also recruit HSPA8/HSC70 to specifically target PRDX1, directing it for degradation via LAMP2A-mediated chaperone-mediated autophagy (CMA). Collectively, these findings demonstrate that the SVA VP2 protein plays a central role in orchestrating both macroautophagy- and CMA-mediated PRDX1 degradation, establishing PRDX1 as a potential intervention target for countering SVA infection.Abbreviations: AKT/protein kinase B: AKT serine/threonine kinase; ATP: adenosine triphosphate; BHK-21: baby hamster kidney-21; CAT: catalase; CCCP: BMDMs: bone marrow-derived macrophages; CMA: chaperone-mediated autophagy; co-IP: co-immunoprecipitation; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CQ: chloroquine; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DMSO: dimethyl sulfoxide; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSH: glutathione; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KO: knockout; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; mM: millimole; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetylcysteine; PI3K: phosphoinositide 3-kinase; PRDX1: peroxiredoxin 1; RT-qPCR: real-time quantitative reverse transcription polymerase chain reaction; ROS: reactive oxygen species; SD: standard deviation; SOD: superoxide dismutase; SQSTM1: sequestosome 1; SVA: Senecavirus A; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type; μg: microgram; μm: micrometer; μM: micromolar.

Keywords: Degradation; PRDX1; SVA VP2 protein; macroautophagy and chaperone-mediated autophagy; reactive oxygen species; viral replication

DOI: https://doi.org/10.1080/15548627.2025.2610449

Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2521070123

L-lactic acid enhances type I interferon immune response and inhibits virus infection by promoting IRF9 L-lactylation.

Ying Miao, Qun Cui, Tingting Zhang, Renxia Zhang, Qian Zhao, Haiyan Zhou, Yibo Zuo, Qin Wang, Yuerong Zhang, Zhijin Zheng, Wei He, Chunyan Liu, Yukang Yuan, Hui Zheng.

Lysine lactylation is a crucial posttranslational modification (PTM) that regulates protein function. Here, this study revealed that L-lactic acid promotes host immune response and inhibits viral infection by inducing Interferon Regulatory Factor 9 (IRF9) L-lactylation. We first found L-lactylation modification (L-Kla) of IRF9 mediated by AARS1. Further studies demonstrated that IRF9 L-lactylation potentiates type I interferon (IFN-I) signaling by promoting IRF9-STAT2 interaction, thereby boosting antiviral immune response. Intriguingly, L-lactic acid exhibits dual effects on viral infection: L-lactic acid exhibits antiviral effects at physiological and moderately elevated levels but proviral effects at high levels. Furthermore, we found that the viruses can achieve immune evasion by promoting SIRT1-mediated delactylation of IRF9. Interestingly, we uncovered that metformin promotes IRF9 L-lactylation by both accumulating lactic acid and disrupting virus-induced IRF9-SIRT1 interaction. These findings renew the understanding of the roles of lactic acid in antiviral immune response and determine metformin's immunomodulatory effects on antiviral immunity through regulating IRF9 L-lactylation.

Keywords: IRF9; L-lactic acid; antiviral immunity; lysine lactylation; metformin

DOI: https://doi.org/10.1073/pnas.2521070123