bims-mevinf 2025-10-19 papers

FEBS Lett. 2025 Oct 13.

Reciprocal control of viral infection and phosphoinositide dynamics.

Phosphoinositides are scarce but dynamic lipids within the cell. They play crucial roles in regulating membrane dynamics and identity, intracellular trafficking, and signal transduction. These functions are coordinated through their distribution and turnover by phosphoinositide-kinases, phosphatases, and lipid-transfer proteins, which also act as key mediators in these processes. Viruses are obligate intracellular pathogens that have developed strategies to hijack the host cellular machinery, including lipid metabolic pathways, to support their replication. During viral infection, they take advantage of phosphoinositides to accomplish various steps of their cycle, such as entry, formation of replication organelles, assembly, and egress. Having such an important role in the viral cycle, targeting phosphoinositide metabolism has emerged as an interesting antiviral strategy over the years. This Review provides insight into the versatility of phosphoinositides during viral infection, presenting their involvement in the viral life cycle, their role as mediators of antiviral immunity, and their potential as a novel approach to antiviral development.

Keywords: antiviral treatment; lipid metabolism; lipid‐transfer protein; phosphoinositide; virus

DOI: https://doi.org/10.1002/1873-3468.70189

Liver Int. 2025 Nov;45(11): e70402

Metabolic Reprogramming and CD8+ T-Cell Exhaustion During Chronic HBV Infection.

Haohao Li, Weiwei Mu, Alison Zhao, Su Xiao, Chenxin Huo, Huajun Zhao, Hongchun Wang, Ronghui Li, Qiuju Han.

HBV is an enveloped DNA virus that exclusively infects hepatocytes of humans and some non-human primates. During its viral life cycle, HBV and its structural components can directly regulate the metabolism of hepatocytes, which may reshape the liver immune microenvironment. CD8+ T-cells, well known as cytotoxic T lymphocytes for their antiviral immunity, can undergo metabolic reprogramming during chronic HBV infection. Increasing evidence demonstrates that metabolic reprogramming promotes T-cell exhaustion, which is a hallmark of HBV infection. Additionally, complicated metabolites (e.g., glucose, lipids, amino acids and nucleic acids) secreted from hepatocytes or T-cells contribute to the communication between these two cell types, which may facilitate HBV infection and hinder antiviral immune response. In recent years, supplementation of certain specific metabolic substrates or targeting metabolic enzyme genes has been reported to mitigate HBV replication and induce antiviral immune response, holding promise as effective strategies for curing chronic HBV infection. This review provides a thorough overview of recent advances in the metabolic characteristics of hepatocytes and T-cells during HBV infection, discusses the relationship between CD8+ T-cell exhaustion and metabolic reprogramming, and emphasises the therapeutic potential of metabolic approaches in the HBV clinical landscape.

Keywords: CD8+ T‐cells; chronic hepatitis B; hepatocytes; immunometabolism; metabolic reprogramming

DOI: https://doi.org/10.1111/liv.70402

Sci Rep. 2025 Oct 17. 15(1): 36390

Anti-dengue activity of a cellular lipid uptake inhibitor, lipofermata.

Songkran Thongon, Chompunuch Boonarkart, Thanyaporn Sirihongthong, Kunlakanya Jitobaom, Nuntaya Punyadee, Radeekorn Akkarawongsapat, Panisadee Avirutnan, Prasert Auewarakul.

There is still no effective antiviral drug for Dengue virus (DENV). Fatty acid (FA) was previously shown to be essential for DENV replication. The availability of intracellular FA depends on both intracellular synthesis and uptake from extracellular sources. While inhibition of FA synthesis has been shown to hinder DENV replication, less is known about inhibition of cellular FA uptake. Fatty acid transporter isoform 2 (FATP2) is known to be highly expressed in hepatocyte, the major target cell of DENV. An immortalized hepatocyte-like cell line (imHC) was used to determine anti-DENV2 activity and FA uptake inhibitory function of Lipofermata (FATP2 inhibitor). FATP2 protein expression level was measured in DENV2-infected cell by western blotting. Finally, Synergistic effect of combination of Lipofermata and Orlistat (FA synthesis inhibitor) was evaluated. Lipofermata could inhibit DENV1 and DENV2 with a 50% inhibitory concentration (IC50) of 1.75 and 1.74 µM, respectively with a similar selectivity index of 3.4. FATP2 expression level was significantly upregulated by DENV2 infection. A combination of Lipofermata with Orlistat, a FA synthesis inhibitor, showed additive or synergistic inhibitory effects on DENV2 in drug synergy prediction models. Cellular FA uptake is therefore a promising target for new anti-DENV drug development.

Keywords: Dengue virus; FATP2; Fatty acid uptake; Lipofermata; Virus-lipid interaction

DOI: https://doi.org/10.1038/s41598-025-20353-7

Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2518975122

Elevated virus infection of honey bee queens reduces methyl oleate production and destabilizes colony-level social structure.

Alison McAfee, Abigail Chapman, Armando Alcazar Magaña, Katie E Marshall, Shelley E Hoover, David R Tarpy, Leonard J Foster.

Pathogenic threats to reproductive individuals pose a profound challenge to the stability of insect societies. In honey bees (Apis mellifera L.), severe virus infections in queens can trigger worker-initiated supersedure, a socially coordinated replacement of the queen that, while risky, is essential when her reproductive competence is compromised. How viruses impact the physiology of queen hosts, who bear unique reproductive burdens within their colonies, and how this perturbs colony social order remains poorly understood. We hypothesized that the supersedure response is mediated by pathogen-induced, intensity-dependent changes in queen pheromonal signaling. Laboratory infection experiments revealed that queens challenged with deformed wing virus B and black queen cell virus infections demonstrated a reduction in methyl oleate, a key component of the queen retinue pheromone, and field data corroborated this association. Lipidomics analysis demonstrated that infection coincides with a systemic lipid deficiency, especially in triacylglycerides (major energy reserves), providing a physiological link among viral stress, ovarian atrophy, and altered pheromone output. Notably, artificial suppression of ovary investment via restricted laying also caused methyl oleate production to decline; therefore, high virus infection likely indirectly suppresses methyl oleate production by reducing ovary mass. In field trials, we further show that synthetic pheromone blends containing methyl oleate significantly suppressed queen cell rearing compared to no-pheromone controls, whereas blends lacking this compound yielded an intermediate effect. These results demonstrate that virus-induced reproductive decline disrupts pheromone signaling, revealing a plausible mechanistic pathway by which pathogens can erode social cohesion.

Keywords: lipid trafficking; pheromones; queen–virus interactions; reproduction; supersedure

DOI: https://doi.org/10.1073/pnas.2518975122

Cell Death Dis. 2025 Oct 13. 16(1): 721

Chronic HBV infection impairs the glucose metabolism and effector function of NK cells via HBsAg/IL-15/mTOR axis.

Yating Yu, Zixuan Wang, Ailu Yang, Yucan Wang, Cuiping Bao, Li Zhuo, Qiuju Han, Huajun Zhao, Jian Zhang.

Natural killer (NK) cell function is impaired in patients with chronic hepatitis B (CHB) infection; however, the underlying mechanisms are not fully understood. Here, we collected the blood samples from healthy donors (HDs) and patients with CHB, and then analyzed the characteristics of NK cells by RNA-seq analysis, flow cytometry, Seahorse assay. HBV-carrier mice were used to confirm the findings in vivo. We found that the dysfunction of NK cells in peripheral blood of patients with CHB was associated with the disturbance of glycolysis. Further investigation showed chronic HBV infection impaired the activation of mammalian target of rapamycin (mTOR) in NK cells, resulting in decreased expression of molecules involved in glycolysis, including HIF-1α and GLUT1. Mechanistically, we found that HBsAg suppressed IL-15-triggered mTOR activity by competitively binding to the IL-15 receptor β (IL-15Rβ, CD122) on NK cells, leading to the decreased expression of HIF-1α and its downstream genes. Significantly, HBsAg neutralizing antibody intravenous injection or mTOR agonist MHY1485 intraperitoneal injection restored the IL-15/mTOR signaling in NK cells of HBV-carrier mice, resulting in NK cell activation and HBV clearance. Further, transferring MHY1485-pretreated NK cells isolated from HBV-carrier mice displayed augmented anti-HBV effects in recipient HBV-carrier mice. These findings reveal a new mechanism by which chronic HBV infection induces NK cell dysfunction, and highlight the potential of mTOR activation and HBsAg clearance as therapeutic strategies for CHB treatment via recovering NK cell immune functions.

DOI: https://doi.org/10.1038/s41419-025-08069-y

J Virol. 2025 Oct 13. e0145625

Protein-S-nitrosylation of adenovirus-5 E1A and human papillomavirus 16 E7 limits their ability to inhibit STING activity.

Justin B Cox, Eain A Murphy.

All viruses that establish successful infections express proteins that inhibit innate anti-viral pathways such as the stimulator of interferon genes (STING) pathway. In response, cells have evolved mechanisms to limit viruses by modifying these viral proteins via post-translational modifications (PTMs). One potent PTM, protein-S-nitrosylation, inhibits the ability of human cytomegalovirus (HCMV) to undermine the establishment of an anti-viral state. The direct nitrosylation of HCMV tegument protein pp71 at a central cysteine within its pRB binding domain reduces pp71's ability to limit the activity of STING. Two different proteins encoded by unrelated DNA viruses, adenovirus (AdV) E1A and human papillomavirus (HPV) E7, also contain a pRB binding domain and inhibit STING like pp71. Herein, we report that E1A and E7 are both protein-S-nitrosylated like pp71. Stable cell lines expressing a WT, or mutants in which the predicted modified cysteine was changed to the closely related serine amino acid, thus blocking protein-S-nitrosylation, revealed that E1A and E7 are both protein-S-nitrosylated. Furthermore, induction of the STING pathway promoted IFN-β1 transcript production and the phosphorylation of IRF3, which was limited in E1A and E7 stable cell lines. Mutant stable cell lines exhibited a stronger inhibition of IFN-β1 transcription and reduced IRF3 phosphorylation, suggesting that the PTM limits WT viral protein inhibition of STING. Furthermore, both E1a and E7 can complement the replication of a HCMV that lacks pp71 during times of STING activation. These observations support a model in which protein-S-nitrosylation of viral virulence factors may function as an anti-viral mechanism in DNA virus infections.IMPORTANCEDNA viruses, such as HCMV, AdV, and HPV, have the capacity to cause significant disease. Infection with AdV can cause severe lower respiratory and liver disease in children, and HPV infection is persistent and is a causative agent of cancer. Thus, these infections can be a severe health risk. Host cells have adapted innate responses like protein S-nitrosylation to limit viral replication. Our previous work reported that direct nitrosylation of two HCMV viral proteins, pp65 and pp71, limits their ability to undermine host anti-viral responses. Herein, we investigated whether protein-S-nitrosylation of AdV and HPV proteins inhibits their functions, suggesting that this PTM is an anti-viral mechanism. This may provide insight into the development of broad anti-viral therapeutics for persistent viral infections.

Keywords: E1a; E7; HCMV; HPV; STING; adenovirus; nitrosylation

DOI: https://doi.org/10.1128/jvi.01456-25