bims-mevinf 2025-05-18 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–05–18
six papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Hypercapnia Increases Influenza A Virus Infection of Bronchial Epithelial Cells by Augmenting Cellular Cholesterol via mTOR and Akt.
PRRSV Nsp4 induces ATGL protein degradation to promote viral replication and lipid droplet accumulation.
Clearance of Hepatitis C Viremia During Direct-Acting Antiviral Therapy Leads to Rapid Changes in Lipid and Lipoprotein Metabolism.
Scale drop disease virus (SDDV) triggers ferroptosis both in mandarin fish (Siniperca chuatsi) and MFF-1 cells to facilitate virus infection via linking to transferrin receptor 1 (TfR1).
Epstein-Barr virus latent membrane protein 1 subverts IMPDH pathways to drive B-cell oncometabolism.
PINLYP-mediated phospholipid metabolism reprogramming contributes to chronic herpesvirus infection.

Int J Mol Sci. 2025 Apr 26. pii: 4133. [Epub ahead of print]26(9):

Hypercapnia Increases Influenza A Virus Infection of Bronchial Epithelial Cells by Augmenting Cellular Cholesterol via mTOR and Akt.

Fei Chen, Aiko Matsuda, Peter H S Sporn, S Marina Casalino-Matsuda.

  Hypercapnia, the elevation of CO2 in blood and tissue, is a risk factor for mortality in patients with severe lung disease and pulmonary infections. We previously showed that hypercapnia increases viral replication and mortality in mice infected with influenza A virus (IAV). Elevated CO2 also augmented cholesterol content and pseudo-SARS-CoV-2 entry in bronchial epithelial cells. Interestingly, cellular cholesterol facilitates IAV uptake, replication, assembly, and egress from cells. Here, we report that hypercapnia increases viral protein expression in airway epithelium of mice infected with IAV. Elevated CO2 also enhanced IAV adhesion and internalization, viral protein expression, and viral replication in bronchial epithelial cells. Hypercapnia increased the expression and activation of the transcription factor sterol-regulatory element binding protein 2 (SREBP2), resulting in elevated expression of cholesterol synthesis enzymes, decreased expression of a cholesterol efflux transporter, and augmented cellular cholesterol. Moreover, reducing cellular cholesterol with an SREBP2 inhibitor or statins blocked hypercapnia-induced increases in viral adhesion and internalization, viral protein expression, and IAV replication. Inhibitors of mTOR and Akt also blocked the effect of hypercapnia on viral growth. Our findings suggest that targeting cholesterol synthesis and/or mTOR/Akt signaling may hold promise for reducing susceptibility to influenza infection in patients with advanced lung disease and hypercapnia.

Keywords:  Akt; cholesterol; hypercapnia; influenza A virus; mTOR

DOI:  https://doi.org/10.3390/ijms26094133
Int J Biol Macromol. 2025 May 09. pii: S0141-8130(25)04649-5. [Epub ahead of print]312 144097

PRRSV Nsp4 induces ATGL protein degradation to promote viral replication and lipid droplet accumulation.

Ermin Xie, Qiumei Wang, Heyou Yi, Jingyu Wang, Xing Liu, Ruirui Ye, Lechen Lu, Tao Tian, Anli Chen, Guoxin Zheng, Guihong Zhang, Heng Wang.

  Porcine reproductive and respiratory syndrome (PRRS) is a prevalent disease caused by porcine reproductive and respiratory syndrome virus (PRRSV). Various viruses regulate lipid metabolism to promote their replication. In this study, we investigated the regulation of the host lipid metabolism by PRRSV. We observed that PRRSV infection induced an increase in intracellular triglyceride (TG) and the accumulation of lipid droplets (LDs). Notably, inhibiting TG synthesis with specific drugs suppressed both PRRSV replication and LD accumulation, whereas supplementation with oleic acid (OA), which increases lipid content, promoted PRRSV replication. Moreover, Western blotting assay revealed a marked reduction in adipose triglyceride lipase (ATGL) expression upon PRRSV infection. The overexpression of ATGL inhibited the increase in intracellular TG and LD accumulation while also suppressing PRRSV replication. In contrast, the knockdown of ATGL induced an increase in intracellular TG, promoting PRRSV replication and enhancing LD accumulation. Western blotting assay indicated that PRRSV infection downregulates the expression of endogenous ATGL. Immunofluorescence and co-immunoprecipitation experiments confirmed that Nsp4 bound to the patatin-like domain of ATGL and inducing its protein degradation. Finally, we demonstrated that Nsp4 induced an increase in intracellular TG and promoted OA-induced LD accumulation, whereas its co-expression with ATGL reduced intracellular TG. In conclusion, we propose that PRRSV Nsp4 induced an increase in intracellular TG by degrading ATGL, thereby promoting PRRSV replication and LD accumulation. These findings provided new insights into the infection mechanism of PRRSV.

Keywords:  ATGL; Lipid droplets; Nsp4; PRRSV; Triglyceride

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144097
Aliment Pharmacol Ther. 2025 May 13.

Clearance of Hepatitis C Viremia During Direct-Acting Antiviral Therapy Leads to Rapid Changes in Lipid and Lipoprotein Metabolism.

Zahra Sarrafan-Chaharsoughi, Varun Takyar, Sungyoung Auh, Gavin Nee, Ahmad Alawad, Brent S Abel, Devika Kapuria, Colleen Byrnes, Anna Wolska, David E Kleiner, Robert Shamburek, Alan T Remaley, Marc G Ghany.

   BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection is associated with hypolipidemia. HCV eradication may, therefore, result in hyperlipidemia and increase cardiovascular disease (CVD) risk. We investigated the impact of HCV eradication on serum lipid and lipoprotein profiles and CVD risk during and following direct-acting antiviral (DAA) therapy.
APPROACH AND RESULTS: We retrospectively analysed stored sera and plasma from 60 DAA-naïve patients, genotypes 1-4, treated with 12 weeks of sofosbuvir-velpatasvir. Serum lipids, apolipoproteins (apo), and a systemic inflammatory marker, GlycA, were measured serially beginning early on treatment and off treatment. Additionally, NMR LipoProfile analysis was performed on plasma samples. Expression of genes regulating lipid metabolism was assessed from paired liver biopsies obtained before and on treatment. Linear mixed models were used to examine changes in lipid and inflammatory markers; Framingham and ASCVD CVD risk scores were assessed before and after treatment. Decline in HCV viremia was associated with a rapid, significant increase in TChol, HDL-C, LDL-C, ApoA-1 and ApoB, and GlycA, improvement in ALT, hepatic inflammation, and steatosis but no change in glycemic control (HOMA-IR and HbA1c). Increase in TChol, LDL-C, and ApoB was associated with an increased SREBP1expression. Both ASCVD and Framingham risk scores were significantly increased at week 24 post treatment after adjusting for age (p < 0.0001).
CONCLUSION: Serum lipids and lipoproteins rapidly increase with inhibition of viral replication during DAA therapy, an effect that may be mediated by genes affecting hepatic de novo lipogenesis. Based on lipid changes, HCV eradication may increase CVD risk, but this needs to be investigated prospectively.

Keywords:  cardiovascular risk; cirrhosis; lipid metabolism; sustained Virological response

DOI:  https://doi.org/10.1111/apt.70130
Fish Shellfish Immunol. 2025 May 13. pii: S1050-4648(25)00305-5. [Epub ahead of print]163 110416

Scale drop disease virus (SDDV) triggers ferroptosis both in mandarin fish (Siniperca chuatsi) and MFF-1 cells to facilitate virus infection via linking to transferrin receptor 1 (TfR1).

Jiaming Chen, Yuting Fu, Shuyi Chen, Shaoping Weng, Jianguo He, Chuanfu Dong.

  Scale drop disease virus (SDDV) is a distinct member in genus Megalocytivirus of family Iridoviridae, garnering increasing attention due to its significant threat to teleost. Ferroptosis is a new type of cell death discovered recently and involved in various viral infections. Knowledges on SDDV induced ferroptosis remains unclear. Here, we demonstrated that SDDV infection triggers ferroptosis, as evidenced by hallmark features such as iron overload, massive lipid peroxides accumulation, glutathione depletion and glutathione peroxidase 4 (gpx4) downregulation. SDDV-infected MFF-1 cells exhibited increased reactive oxygen species production and mitochondrial shrinkage. Treatment with Ferrostatin-1, a potent ferroptosis inhibitor, significantly attenuated SDDV replication in MFF-1 cells and could improve the survival of mandarin fish upon SDDV challenge. Treatment with an iron chelator mitigated ferroptosis and reduced the mortality of mandarin fish following SDDV infection, suggesting that SDDV-induced ferroptosis is iron-dependent. Finally, we demonstrated that SDDV infection could upregulate the expression of transferrin receptor protein 1 (TfR1), a critical iron transporter, to disrupt cellular iron homeostasis, induce ferroptosis, and then facilitate viral infection. Collectively, our findings provide compelling evidence that SDDV infection induces ferroptosis by targeting TfR1 to facilitate virus infection. Inhibiting ferroptosis maybe represent a promising anti-viral strategy for combating SDDV infection in aquaculture.

Keywords:  Ferroptosis; Infectivity; Scale drop disease virus (SDDV); Transferrin receptor protein 1 (TfR1)

DOI:  https://doi.org/10.1016/j.fsi.2025.110416
PLoS Pathog. 2025 May 14. 21(5): e1013092

Epstein-Barr virus latent membrane protein 1 subverts IMPDH pathways to drive B-cell oncometabolism.

Eric M Burton, Davide Maestri, Shaowen White, Jin-Hua Liang, Bidisha Mitra, John M Asara, Benjamin E Gewurz.

Epstein-Barr virus (EBV) is associated with multiple types of cancers, many of which express the viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 contributes to both epithelial and B-cell transformation. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism. To gain insights into key B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells with conditional LMP1 expression. This approach highlighted that LMP highly induces de novo purine biosynthesis, with xanthosine-5-P (XMP) as one of the most highly LMP1-upregulated metabolites. Consequently, IMPDH inhibition by mycophenolic acid (MPA) triggered death of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), a key model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest of Burkitt lymphoma cells with the EBV latency I program, conditional LMP1 expression triggered their death, and this phenotype was rescuable by guanosine triphosphate (GTP) supplementation, implicating LMP1 as a key driver of B-cell GTP biosynthesis. Although both IMPDH isozymes are expressed in LCLs, only IMPDH2 was critical for LCL survival, whereas both contributed to proliferation of Burkitt cells with the EBV latency I program. Both LMP1 C-terminal cytoplasmic tail domains critical for primary human B-cell transformation were important for XMP production, and each contributed to LMP1-driven Burkitt cell sensitivity to MPA. Metabolomic analyses further highlighted roles of NF-kB, mitogen activated kinase and protein kinase C downstream of LMP1 in support of XMP abundance. Of these, only protein kinase C activity was important for supporting GTP levels in LMP1 expressing Burkitt cells. MPA also de-repressed EBV lytic antigens, including LMP1 itself in latency I Burkitt cells, highlighting crosstalk between the purine biosynthesis pathway and the EBV epigenome. These results suggest novel oncometabolism-based therapeutic approaches to LMP1-driven lymphomas.

DOI: https://doi.org/10.1371/journal.ppat.1013092
PLoS Pathog. 2025 May;21(5): e1013146

PINLYP-mediated phospholipid metabolism reprogramming contributes to chronic herpesvirus infection.

Zhangmengxue Lei, Wendi Wei, Mingyu Wang, Yun Xu, Lei Bai, Ying Gao, Congwei Jiang, Fangxia Li, Na Tian, Linlin Kuang, Ruiliang Zhu, Gang Pang, Ke Lan, Suihan Feng, Xiaozhen Liang.

Many viruses alter the phospholipid metabolism to benefit their own life cycles. It is unclear whether the host or the virus is driving phospholipid metabolism reprogramming, and how virus infections are affected by the metabolic status. Here we report that phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein (PINLYP) inhibits Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation by remodeling phospholipid metabolism and especially triacylglycerol (TAG) biosynthesis. PINLYP deficiency led to increased phospholipase cPLA2α activity, cPLA2α-mediated AKT phosphorylation, and KSHV lytic reactivation. Analyses of RNA-seq and lipidomics reveal that PINLYP regulates long-chain fatty acid CoA ligase ACSL5 expression and TAG production. The inhibition of ACSL5 activity or TAG biosynthesis suppresses AKT phosphorylation and KSHV lytic reactivation, restoring the phenotype of PINLYP deficiency. This finding underscores the pivotal role of PINLYP in remodeling phospholipid metabolism and promoting viral latency, which sheds new light on how phospholipid metabolism is regulated by herpesvirus and provides a potential target for controlling chronic herpesvirus infection.

DOI: https://doi.org/10.1371/journal.ppat.1013146