bims-mevinf 2025-06-08 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–06–08
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Newcastle disease virus induces degradation of folliculin to regulate host cell energy metabolism and facilitate viral replication.
Pexophagy-driven redox imbalance promotes virus-induced ferroptosis.
COP I vesicles facilitate classical swine fever virus proliferation by transporting fatty acid synthase from the Golgi apparatus to the endoplasmic reticulum.
Impact of HCV elimination on metabolism markers in people living with HIV.
Interferon-stimulated gene MCL1 inhibits foot-and-mouth disease virus replication by modulating mitochondrial dynamics and autophagy.
Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses.
Urine metabolomic analyses reveal metabolite disruptions in steroid hormone biosynthesis in monkeypox.
The Tryptophan-Kynurenine pathway in people living with HIV: a systematic review.
The role of immune checkpoint molecules in PRRSV-2-induced immune modulation: insights from comparative in vivo evaluation including NADC34-like PRRSV.

Poult Sci. 2025 May 23. pii: S0032-5791(25)00557-7. [Epub ahead of print]104(8): 105314

Newcastle disease virus induces degradation of folliculin to regulate host cell energy metabolism and facilitate viral replication.

Mengqing Yang, Xianjin Kan, Xinna Li, Yingjie Sun, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Chan Ding.

  Viral replication is an energy-intensive process that often induces energy stress in host cells, and efficient mobilization of host cell energy resources facilitates optimal viral replication. The mechanisms by which Newcastle disease virus (NDV) regulates the host energy metabolism to facilitate its replication remain incompletely understood. For this purpose, transcriptomic analysis was conducted to delineate the transcriptional changes during NDV infection. The results demonstrated that NDV infection downregulated the transcriptional levels of enzymes associated with de novo fatty acid synthesis. Subsequent investigations demonstrated that the active form of the sterol regulatory element-binding protein 1c (SREBP1c) a master transcription factor governing lipid biosynthesis pathways, exhibits reduced expression following viral infection. Notably, SREBP1c activation is negatively regulated by folliculin (FLCN), a tumor suppressor protein that undergoes during NDV infection. The de novo fatty acid synthesis pathway is an energy-intensive process, and the degradation of FLCN may suppress this pathway to maintain cellular energy homeostasis, thereby supporting viral replication. In summary, our findings demonstrate that NDV facilitates its replication by inducing degradation of FLCN, thereby modulating the host cell energy metabolism.

Keywords:  De novo fatty acid synthesis; Energy metabolism; FLCN; NDV; SREBP1c

DOI:  https://doi.org/10.1016/j.psj.2025.105314
Cell Rep. 2025 Jun 04. pii: S2211-1247(25)00554-6. [Epub ahead of print]44(6): 115783

Pexophagy-driven redox imbalance promotes virus-induced ferroptosis.

Hui Jiang, Yang Qu, Xianjin Kan, Mengqing Yang, Yabin Gong, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Venugopal Nair, Chan Ding, Yingjie Sun.

  Peroxisomes are critical organelles that maintain cellular redox homeostasis. Many viruses induce oxidative stress and degrade peroxisomes, but the mechanisms and consequences remain unclear. In this study, we systematically investigate how virus-induced pexophagy regulates peroxisome homeostasis. Using Newcastle disease virus (NDV) as a model, we demonstrate that NDV infection triggers excessive reactive oxygen species (ROS) production, activating the phosphorylation and peroxisomal localization of ataxia-telangiectasia mutated (ATM). Activated ATM promotes the interaction between the peroxisomal receptor PEX5 and the autophagy receptor p62, driving pexophagy. Pexophagy-mediated peroxisome degradation leads to excess active iron and ROS accumulation, contributing to NDV-induced ferroptosis. Notably, this mechanism is shared by other viruses, such as vesicular stomatitis virus and H9N2 avian influenza virus. Our study provides insights into how virus-induced pexophagy disrupts redox homeostasis to promote ferroptosis, highlighting a link between viral infection, peroxisome degradation, and programmed cell death.

Keywords:  CP: Immunology; CP: Microbiology; PEX5; ROS; ferroptosis; peroxisome; pexophagy; virus

DOI:  https://doi.org/10.1016/j.celrep.2025.115783
J Virol. 2025 Jun 03. e0030525

COP I vesicles facilitate classical swine fever virus proliferation by transporting fatty acid synthase from the Golgi apparatus to the endoplasmic reticulum.

Liang Zhang, Tao Wang, Chen Chen, Mengzhao Song, Ning Li, Bihao Luo, Yuehan Quan, Kangkang Guo, Yanming Zhang.

  Classical swine fever virus (CSFV) is an enveloped, positive-sense, single-stranded RNA virus in the Flaviviridae family that remodels the cell's endomembrane for its own propagation. The early secretory pathway is exploited by viruses for their lifecycle, but the mechanism underlying this hijacking of the early secretory pathway in CSFV infection remains unknown. Here, we observed that disrupting the functions of the early secretory pathway organelles, the Golgi apparatus, the endoplasmic reticulum (ER), and coatomer protein I (COP I) vesicles and coatomer protein II (COP II) vesicles resulted in a significant inhibition of CSFV propagation. Further, we revealed that COP I vesicles were required for CSFV RNA replication, but not for the formation of viral replication complexes. The results support the hypothesis that participation of COP I vesicles in viral RNA replication involves their capacity for cargo trafficking. Intact COP I vesicles were isolated and subjected to data-independent acquisition quantitative proteomics analysis to identify the differences in the proteomes of COP I vesicles. This analysis revealed an increase in fatty acid synthase (FASN), a critical factor for CSFV RNA replication, within COP I vesicles, while its presence in COP II vesicles decreased in CSFV-infected cells. Meanwhile, blocking COP I vesicle formation resulted in decreased levels of FASN in the ER, impairing CSFV RNA replication. Collectively, we provide evidence that COP I vesicles mediate FASN trafficking from the Golgi apparatus to the ER to facilitate CSFV RNA replication, which advances our understanding of the role of the early secretory pathway in CSFV proliferation.IMPORTANCEClassical swine fever is a highly contagious disease caused by the classical swine fever virus (CSFV) that infects domestic pigs and wild boars and results in significant economic losses to the swine industry. The early secretory pathway in host cells has often been hijacked by viruses for viral genome replication, assembly, and release of virions. Here, our data revealed that the function of early secretory pathway organelles such as the endoplasmic reticulum (ER) and the Golgi apparatus, and the membrane-bound transport intermediates, COP I vesicles and COP II vesicles, that facilitate transport, were involved in CSFV proliferation in PK-15 cells. Our findings demonstrate that COP I vesicles significantly promote CSFV RNA replication by trafficking fatty acid synthase from the Golgi apparatus to the ER. Our data suggest that manipulation of early secretory pathway function in target host cells could provide a promising strategy for a novel anti-CSFV therapeutic.

Keywords:  classical swine fever virus; coatomer protein I; coatomer protein II; early secretory pathway; fatty acid synthase

DOI:  https://doi.org/10.1128/jvi.00305-25
Sci Rep. 2025 May 29. 15(1): 18937

Impact of HCV elimination on metabolism markers in people living with HIV.

Multidisciplinary HIV/Hepatitis Viral Coinfection Group (COHIVEP)

  Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) alter lipid and glucose metabolism mediated by cytokines release. Our aim was to assess the evolution in metabolic plasmatic markers of people living with HIV (PLHIV) after HCV elimination either spontaneously or with direct active antivirals (DAAs). Multicenter prospective study of 116 HIV patients: i) HCV chronically infected patients (CHC) = 45; ii) Spontaneous clarifiers (SC) = 36; and iii) HIV control group = 35. HCV-exposed patients were all studied at baseline and 48 weeks after achieving sustained virological response (SVR). Plasma levels of 14 metabolic biomarkers were measured. Differences between groups were evaluated by statistical methods. At baseline, CHC patients showed higher levels of adiponectin, NGAL and sICAM-1, than the control group. After achieving SVR, the CHC group showed a significant decrease in the 3 cytokines that were increased at baseline: adiponectin, NGAL and sICAM. In contrast, there was an increase in cortisol. After the end of the follow-up CHC showed normalization of all measured markers that were increased at baseline. Any changes were observed in the same follow-up period for the SC group. Chronically coinfected HIV + /HCV + patients showed altered levels in lipid and glucose metabolism compared to HIV monoinfected subjects and spontaneous clearers. The elimination of chronic HCV infection by DAAs normalized the metabolism profile except for cortisol that remains increased after reaching RSV compared to levels observed in the HCV-/HIV + group. Spontaneous clarification of HCV did not modify metabolism biomarkers in these patients.

Keywords:  DAAs; HCV/HIV; Metabolism markers; Spontaneous viral clearance

DOI:  https://doi.org/10.1038/s41598-025-99107-4
J Virol. 2025 Jun 04. e0058125

Interferon-stimulated gene MCL1 inhibits foot-and-mouth disease virus replication by modulating mitochondrial dynamics and autophagy.

Aishwarya Mogulothu, Danielle Hickman, Sarah Attreed, Paul Azzinaro, Monica Rodriguez-Calzada, Meike Dittmann, Teresa de Los Santos, Steven Szczepanek, Gisselle N Medina.

  Interferons (IFNs) and the IFN-stimulated genes (ISGs) that they induce are effective in reducing the replication of foot and mouth disease virus (FMDV). The use of a high-throughput ISG screen identified the ISG myeloid cell leukemia 1 (MCL1) as an ISG with an antiviral effect against an FMDV replicon system. In this study, we demonstrated that overexpression of MCL1 inhibits FMDV replication by reducing approximately 4 logs of virus titers in porcine cells. We then explored the regulatory pathways associated with MCL1 to determine the specific antiviral mechanisms against FMDV. Our findings indicated that the antiviral mechanism does not involve apoptosis regulation or alterations in cell cycle phase heterogeneity. Analysis of mitochondrial function, through measurement of mitochondrial oxygen consumption rate, demonstrated that overexpression of MCL1 results in increased mitochondrial respiration and ATP production, whereas FMDV infection reduces both processes. Moreover, MCL1 overexpression resulted in elongated mitochondrial morphology, contrasting with the fragmented and punctate morphology observed during FMDV infection. Importantly, these changes in mitochondrial dynamics were independent of MCL1's regulation of mitochondrial calcium flux. We also found that MCL1 overexpression suppresses autophagy, which is known to be necessary for FMDV replication. Our data indicate that MCL1 is a potent antiviral ISG against FMDV and highlight the importance of mitochondrial dynamics and autophagy in FMDV replication.IMPORTANCEIn this study, we have successfully used a high-throughput ISG screening approach to measure the inhibition of FMDV replication using an RNA replicon system for the first time. This screen led to the identification of the potent antiviral effects of a relatively lesser-known ISG called MCL1. Our findings reveal that MCL1 exerts its antiviral functions through the regulation of mitochondrial dynamics and autophagy. Although mitochondrial dynamics are involved in apoptosis, metabolism, redox homeostasis, stress responses, and antiviral signaling, this pathway has not been thoroughly explored in the context of FMDV infection. Further investigation into mitochondrial dynamics may facilitate the development of improved biotherapeutics for FMDV. Additionally, our studies highlight the significance of autophagy, a pathway that is needed by FMDV for replication. Ultimately, a deep understanding of all mechanisms exploited by FMDV may allow for the rational design of novel therapeutics and vaccines to control FMD.

Keywords:  antiviral agents; autophagy; foot-and-mouth disease virus; interferon-stimulated genes; interferons; mitochondrial metabolism

DOI:  https://doi.org/10.1128/jvi.00581-25
Front Immunol. 2025 ;16 1578202

Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses.

Mahmoud Darweesh, Saeed Mohammadi, Mina Rahmati, Moosa Al-Hamadani, Ahmed Al-Harrasi.

  Metabolic reprogramming is an important player within the immune response to viral infections, allowing immune cells to fine-tune their energy production and biosynthetic requirements while it is actively working to restrict pathogen access to essential nutrients. Particularly, glucose metabolism, which appears to be one of the important regulators of immune function, affects immune cell activation, cytokine secretion, and pathogen restriction. This review explores the mechanisms of metabolic reprogramming during viral infections, with a specific emphasis on glucose metabolism. We discussed the key cytokines involved in orchestrating this metabolic process and the influence of pre-existing metabolic disorders on immune efficiency. Furthermore, we introduced emerging therapeutic strategies that target glucose metabolism to enhance antiviral immunity and improve disease outcomes. A deeper understanding of the interaction between metabolism and immunity could be promising for the development of novel immunometabolic targets against viral infections.

Keywords:  cytokines; diabetes; glucose metabolism; immune activation; immunometabolism; pathogen clearance; viral infections

DOI:  https://doi.org/10.3389/fimmu.2025.1578202
iScience. 2025 Jun 20. 28(6): 112554

Urine metabolomic analyses reveal metabolite disruptions in steroid hormone biosynthesis in monkeypox.

Xiaofeng Yang, Huiqin Yang, Chudan Liang, Fei Tang, Zhenyu Long, Linjin Fan, Yulong Wang, Zequn Wang, Mou Zeng, Weifang Kang, Pengfei Ye, Wendi Shi, Yuandong Zhou, Jingyan Lin, Hongxin Huang, Huijun Yan, Jian Wang, Linghua Li, Jun Qian, Linna Liu.

  Monkeypox virus (MPXV) poses a global health threat. Viral infection can alter host metabolic homeostasis, while its changes may influence disease severity and progression. The relationship between MPXV and metabolites has not been reported. we employed metabolomics to characterize the mpox specific metabolic features by comparing changes in urinary metabolites from patients with MPXV infection, HIV infection, and HIV-MPXV co-infection. The metabolic changes caused by MPXV were mainly concentrated in amino acid and hormone metabolism. Further analysis showed that 5'-dihydroadenosine and uric acid can serve as potential molecular markers for MPXV and HIV-MPXV co-infected patients, respectively. Confirmed by targeted metabolomics and ELISA methods, MPXV infection caused severe disorders in the metabolic pathways of steroid hormones such as testosterone and progesterone in humans. Our findings identify dysregulated metabolism as an underpinning of MPXV pathogenicity, and increasing the anti-inflammatory capacity of patients may play a role to some extent against mpox.

Keywords:  Metabolomics; Virology

DOI:  https://doi.org/10.1016/j.isci.2025.112554
Infection. 2025 May 31.

The Tryptophan-Kynurenine pathway in people living with HIV: a systematic review.

Tshiamo Will Sebigi, Levanco K Asia, Grant G January, Esmé Jansen van Vuren, Monray Edward Williams.

   PURPOSE: HIV-1 disrupts the metabolic profile of people living with HIV (PLWH), including the Tryptophan-Kynurenine (Trp-Kyn) pathway, linked to disease outcomes and comorbidities. Despite numerous studies, consensus on key dysregulated metabolites in antiretroviral therapy (ART)-treated PLWH is lacking. This systematic review compiles data to identify and highlight the most noteworthy Trp-Kyn metabolites.
METHODS: PubMed, Scopus, and Web of Science databases were searched using a search protocol specifically designed for this study. Studies that investigated the levels of metabolites in the Trp-Kyn pathway in the peripheral blood of PLWH on ART, as well as in healthy control groups were included.
RESULTS: Thirteen metabolomic studies that investigated this pathway met our inclusion criteria. The findings revealed that Trp, Kyn, and the Kyn/Trp ratio (indicative of indoleamine 2,3-dioxygenase IDO activity) were the most investigated metabolites in this metabolic pathway. Evidence consistently demonstrated that Trp levels were lower in PLWH, while predicted IDO activity was consistently higher. Despite the widespread investigation of Kyn, there was no clear consensus on its levels in PLWH, with some studies reporting higher levels and others finding no significant differences compared to HIV-negative controls.
CONCLUSION: In the modern ART era, Trp metabolism and IDO activity may play key regulatory roles in HIV-1 pathogenesis, as evidenced by the consistent patterns observed across various studies. These metabolites and related pathways warrant further investigation as potential targets for improved diagnostics, prognostics, and therapeutics in the context of HIV-1.

Keywords:  Antiretroviral therapy; Biomarkers; Immunometabolism; Metabolite dysregulation; Metabolomics

DOI:  https://doi.org/10.1007/s15010-025-02557-1
J Virol. 2025 Jun 03. e0229824

The role of immune checkpoint molecules in PRRSV-2-induced immune modulation: insights from comparative in vivo evaluation including NADC34-like PRRSV.

Seung-Chai Kim, Hwan-Ju Kim, Sang Chul Kang, Aarif Rasool, Ji-Hyun Ryu, Jung-Min Lee, Won-Il Kim.

  The emergence of genetically diverse PRRSV-2 lineages, including the NADC34-like virus, presents significant challenges to the swine industry due to their variable pathogenicity and impact on immune modulation. However, the precise mechanisms underlying virus-induced immune modulation remain poorly understood. This study investigated the immunopathological characteristics of the Korean NADC34-like PRRSV strain JBNU-22-N01 in comparison with the NADC30-like strain PJ73 and the prototype strain VR2332 in a weaned piglet model. All PRRSV-2 strains exhibited moderate pathogenicity without mortality, following a similar infection course characterized by interstitial pneumonia, cytokine cascades (e.g., IFN-α, IFN-γ, IL-1β, IL-12p40, IL-10, CCL2, CCL5, CCL8, and CXCL10), and upregulation of interferon-stimulated genes [e.g., ISG12(A)]. Flow cytometry analysis revealed significant alterations in the composition of bronchoalveolar lavage (BAL) cell populations, including a decreased frequency of alveolar macrophages and an increased proportion of infiltrating immune cells (monocyte-derived cells, T cells, and NK cells). However, the majority of infiltrated CD4+ and CD8+ T cells exhibited minimal expression of effector cytokines (e.g., IFN-γ), suggesting a phenotypically naïve-like or functionally unresponsive state. The mRNA expression levels of BAL cells revealed significant upregulation of immune checkpoint molecules (e.g., PD1, PDL1, CTLA4, LAG3, and IDO1), indicating immune regulation potentially mediated through cell-to-cell communication. Notably, IDO1 expression was modestly associated with increased systemic Kyn/Trp ratios, supporting the hypothesis that the kynurenine pathway may contribute to systemic immune modulation during PRRSV infection. From a strain-specific perspective, JBNU-22-N01 displayed a faster replication rate, resulting in an accelerated and heightened infection process with stronger immune responses. It uniquely induced robust expression of immune checkpoint molecules and enhanced IDO1 protein production in bronchoalveolar lavage cells, highlighting the immunomodulatory potential of NADC34-like PRRSV. These findings offer insights into both general and strain-specific immunopathogenesis of PRRSV-2 and support the development of better treatments.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) is a major pathogen affecting the swine industry; however, its immune-related mechanisms remain incompletely understood. Here, we analyzed how three genetically distinct PRRSV strains, including the globally prevalent NADC34-like strain, interact with the immune system in piglets. Our results showed that PRRSV induces severe lung inflammation accompanied by immune cell infiltration. However, many infiltrating immune cells remained inactive, likely due to increased expression of immune-suppressive molecules. Among these, the enzyme indoleamine 2,3-dioxygenase-1 (IDO1) was notably upregulated, activating a metabolic pathway linked to immune regulation and suppression. The NADC34-like strain displayed a faster replication rate, leading to more rapid immune responses and stronger suppression compared with the other strains. These findings provide new insights into how PRRSV manipulates the immune system and suggest potential targets for improved prevention and treatment strategies.

Keywords:  IDO1; NADC34; PRRSV; immune checkpoint molecules; immunopathogenesis; immunosuppression; kynurenine pathway; pathogenicity; porcine reproductive and respiratory syndrome virus

DOI:  https://doi.org/10.1128/jvi.02298-24