bims-mevinf 2025-04-27 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–04–27
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.
Enhancement of reactive oxygen species metabolism by antioxidant enzyme Cu/Zn-SOD can block betanodavirus-induced necroptosis and suppress viral replication in fish cells.
Effect of Nrf2 Activators in Hepatitis B Virus-Infected Cells Under Oxidative Stress.
Orthoflavivirus infection and the mTOR signaling pathway.
LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.
Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by enzyme activity-dependent and direct interaction with nucleocapsid protein.
Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.
Bombyx mori nuclear polyhedrosis virus infection regulated by host glycosphingolipids.
Antiviral activity of eicosapentaenoic acid against zika virus and other enveloped viruses.
IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.

Cell Commun Signal. 2025 Apr 22. 23(1): 191

Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.

Cong-Yan Chen, Chih-Ling Chen, Yen Siong Ng, Der-Yen Lee, Shih-Shun Lin, Chien-Kang Huang, Ramya Kumar, Han-Ching Wang.

   BACKGROUND: Viruses rely on host metabolism to complete their replication cycle. White spot syndrome virus (WSSV), a major pathogen in shrimp aquaculture, hijacks host metabolic pathways to fulfill its biosynthetic and energetic needs. Previous studies have demonstrated that WSSV promotes aerobic glycolysis (Warburg effect) and glutaminolysis during its replication stage (12 hpi). Therefore, glucose and glutamine serve as crucial metabolites for viral replication. Additionally, de novo nucleotide synthesis, including the pentose phosphate pathway and purine/pyrimidine synthesis, is significantly activated during WSSV infection. However, the precise association between WSSV and host glucose and glutamine metabolism in driving de novo nucleotide synthesis remains unclear. This study aimed to investigate the involvement of glucose and glutamine in nucleotide metabolism during WSSV replication and to elucidate how WSSV reprograms these pathways to facilitate its pathogenesis.
METHODS: To assess changes in metabolic flux during WSSV replication, LC-ESI-MS-based isotopically labeled glucose ([U-13C] glucose) and glutamine ([A-15N] glutamine) were used as metabolic tracers in in vivo experiments with white shrimp (Litopenaeus vannamei). The in vivo experiments were also conducted to measure the expression and enzymatic activity of genes involved in nucleotide metabolism. Additionally, in vivo dsRNA-mediated gene silencing was employed to evaluate the roles of these genes in WSSV replication. Pharmacological inhibitors targeting the Ras-PI3K-Akt-mTOR pathway were also applied to investigate its regulatory role in WSSV-induced nucleotide metabolic reprogramming.
RESULTS: The metabolite tracking analysis confirmed that de novo nucleotide synthesis was significantly activated at the WSSV replication stage (12 hpi). Glucose metabolism is preferentially reprogrammed to support purine synthesis, while glutamine uptake is significantly increased and contributes to both purine and pyrimidine synthesis. Consistently, gene expression and enzymatic activity analyses, along with gene silencing experiments, indicated the critical role of de novo nucleotide synthesis in supporting viral replication. However, while the inhibition of the Ras-PI3K-Akt-mTOR pathway suggested its involvement in regulating nucleotide metabolism, no consistent effect on WSSV replication was observed, suggesting the presence of alternative regulatory mechanisms.
CONCLUSION: This study demonstrates that WSSV infection induces specific metabolic reprogramming of glucose and glutamine utilization to facilitate de novo nucleotide synthesis in shrimp. These metabolic changes provide the necessary precursors for nucleotide synthesis, supporting WSSV replication and pathogenesis. The findings offer novel insights into the metabolic strategies employed by WSSV and suggest potential targets for controlling WSSV outbreaks in shrimp aquaculture.

Keywords:  Pentose phosphate pathway; Warburg effect; White shrimp; White spot syndrome virus; de novo nucleotide metabolism; in vivo stable-isotope tracing metabolomics

DOI:  https://doi.org/10.1186/s12964-025-02186-z
Fish Shellfish Immunol. 2025 Apr 18. pii: S1050-4648(25)00233-5. [Epub ahead of print]162 110344

Enhancement of reactive oxygen species metabolism by antioxidant enzyme Cu/Zn-SOD can block betanodavirus-induced necroptosis and suppress viral replication in fish cells.

Hong-Jun Liao, Jiann-Ruey Hong.

  Very little is known about oxidative stress as a modulator of signaling between the host and virus in viral nervous necrosis (VNN) within the aquaculture field. In the present study, we examined whether blocking ROS signaling using mitochondrial Cu/Zn-SOD could affect host cell death and the viral replication of RGNNV during infection in fish cells. Upon the overexpression of Cu/Zn-SOD in fish GF-1 cells, superoxide generation in RGNNV infection was reduced 0.6-fold, which correlated to host cell viability in the middle-late stages. Regarding the regulation of reactive oxygen species (ROS) signaling by superoxide, Cu/Zn-SOD overexpression can enhance superoxide's metabolism to hydrogen peroxide, which suppresses the RIPK3-mediated cell death signals at 48 hpf. On the other hand, ROS-mediated signal suppression can enhance Bcl-2 family Bcl-2/Bcl-xL expression in the early and middle replication stages. Furthermore, the enhancement of superoxide metabolism can reduce the virus' replication ability and expression of the non-structural genes B1 and B2, as well as the genome replication gene Protein A and the major capsid protein protein α, which were correlated with the viral load dropping by two log viral titers at 48 and 72 hpf. Taken together, these data suggest that ROS signals trigger host stress responses related to cell death/necroptosis in RGNNV infection. Then, ROS-mediated stress signals can modulate anti-cell death signals through the Bcl-2/Bcl-xL pathway. In conclusion, an ROS-mediated stress response is required for viral expression and replication cycles, providing new insights into controlling RNA viruses.

Keywords:  Antioxidant enzyme Cu/Zn-SOD; Necroptosis; Nervous necrosis virus; Oxidative stress; Viral replication

DOI:  https://doi.org/10.1016/j.fsi.2025.110344
Mar Drugs. 2025 Apr 03. pii: 155. [Epub ahead of print]23(4):

Effect of Nrf2 Activators in Hepatitis B Virus-Infected Cells Under Oxidative Stress.

Junsei Taira, Takuya Kubo, Hiroya Nagano, Ryuji Tsuda, Takayuki Ogi, Kenji Nakashima, Tetsuro Suzuki.

  The liver is an active metabolic site that generates high levels of reactive oxygen species (ROS). Oxidative stress has been implicated in the chronicity of hepatitis and hepatitis B virus (HBV) infection. This study aimed to determine the involvement of oxidative stress in HBV-infected cells and the efficacy of natural Nrf2 activators. The intracellular HBV pregenomic RNA copy number relative to total RNA was measured by RT-PCR, and various protein expressions associated with oxidative stress were analyzed by a Western blot analysis. The results showed that the Nrf2, HO-1, Akt, and Bcl-xL proteins were decreased by the continuous infection, indicating that HBV-positive cells were exposed to oxidative stress. The present study evaluated the anti-HBV infection effects of the Nrf2 activator fucoxanthin (Fx), a marine carotenoid from edible biological resources, including the comparative natural Nrf2 activator pteryxin (Ptx). These Nrf2 activators suppressed the HBV pregenomic RNA production in the HBV-infected cells, thus increasing the expression of the proteins of Nrf2 and HO-1. In the persistently infected cells transfected with the HBV genome, the Bcl-xL and Keap1 proteins, which contribute to suppressing the HBx protein involved in the HBV replication, were overexpressed. In particular, the activity of these protein expressions was marked at low concentrations of Fx. This suggests that natural Nrf2 activators may play a significant role in the HBV infection and could be a valuable source for further development through the functional utilization of food resources.

Keywords:  HBV (hepatitis B virus); Nrf2/ARE signaling; fucoxanthin; oxidative stress; pregenomic RNA; pteryxin

DOI:  https://doi.org/10.3390/md23040155
Front Microbiol. 2025 ;16 1565350

Orthoflavivirus infection and the mTOR signaling pathway.

Yahui Zhang, Jianbo Ba, Jie Luan, Zhongtian Qi, Bin Liu.

  Each year, mosquito-borne orthoflaviviruses, including Zika virus, dengue virus, and the Japanese encephalitis virus, threaten the health of more than 400 million people worldwide. To date, knowledge about the pathogenic mechanisms underlying orthoflavivirus infection and the interactions of these viruses with host cells is limited. Mammalian target of rapamycin (mTOR) is pivotal for cell growth and metabolism. The downstream targets of mTOR regulate protein translation and cell autophagy to affect orthoflavivirus replication, and its upstream protein AKT performs similar functions. In this work, the mechanism underlying the relationship between the mTOR signaling pathway and orthoflavivirus infection was reviewed from three perspectives: orthoflavivirus structure and life cycle, mTOR structure and signaling pathway, and regulation of the mTOR signaling pathway during orthoflavivirus infection.

Keywords:  Zika virus; dengue virus; mTOR signaling pathway; orthoflavivirus; viral replication

DOI:  https://doi.org/10.3389/fmicb.2025.1565350
J Virol. 2025 Apr 23. e0026825

LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.

Sen Zeng, Zipeng Luo, Wenhui Zhu, Zhanhui Zhang, Ruibo Zhao, Shuaiqi Zhu, Qi Qiu, Nan Cao, Xinliang Fu, Wenjun Liu, Shuangqi Fan, Cheng Fu.

  Lactate dehydrogenase A (LDHA) plays a crucial role in regulating lactate synthesis in various biological processes. Lactate, a byproduct of glycometabolism, has been recognized as a unique molecule with implications in both metabolism and immunity. Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and severe infectious disease that primarily affects pigs. Prior research has shown that CSFV infection disrupts the normal glycolytic process, leading to an accumulation of lactate within the host. Nevertheless, it remains unclear whether there is mutual regulation between the CSFV and LDHA-lactate axis. Here, we have found that CSFV infection increases LDHA expression in vivo and in vitro, which may be attributed to attenuated ISGylation of LDHA. Furthermore, CSFV infection induces L-lactate production via LDHA dependence in vitro. The cellular biology research on LDHA has revealed that LDHA not only localizes to the mitochondria but also inhibits PINK1-Parkin-mediated mitophagy. Through various experimental techniques such as western blot to detect mitophagy marker proteins, laser confocal microscopy to observe the flow of mitophagy, and transmission electron microscopy to assess changes in the number of mitochondria enclosed within autophagosome-like vesicles, it has been discovered that the addition of exogenous lactate can inhibit PINK1-Parkin-mediated mitophagy. Importantly, we have observed that lactate activates the JAK1-STAT1-ISG15 network and suppresses CSFV replication by antagonizing CCCP-induced mitophagy. These results represent the first report on the mechanisms through which the LDHA-lactate axis regulates mitophagy, the JAK-STAT pathway, and CSFV replication. This study provides novel insights into the roles of the LDHA-lactate axis in glycometabolism and viral replication.
IMPORTANCE: This research unveils how CSFV interacts with cellular metabolism through LDHA. By revealing LDHA's dual role and how lactate influences cellular processes during CSFV infection, this study uncovers new pathways for viral replication. These findings not only deepen our understanding of viral-host interactions but also open doors for innovative antiviral strategies centered around manipulating cellular metabolism.

Keywords:  CSFV; JAK-STAT; LDHA; lactate; mitophagy

DOI:  https://doi.org/10.1128/jvi.00268-25
J Virol. 2025 Apr 22. e0042825

Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by enzyme activity-dependent and direct interaction with nucleocapsid protein.

Guangmei Zhu, Xianchun Zong, Mengmeng Xiao, Dan Wang, Zhe Xu, Jingtao Hu, Guilian Yang, Yanlong Jiang, Wentao Yang, Haibin Huang, Chunwei Shi, Yan Zeng, Nan Wang, Xin Cao, Jianzhong Wang, Chunfeng Wang.

  Newcastle disease virus (NDV) is a significant enveloped virus within the Paramyxoviridae family, posing a major threat to the global poultry industry. Increasing evidence suggests that cholesterol-25-hydroxylase (CH25H) and its enzymatic product, 25-hydroxycholesterol (25HC), exhibit broad-spectrum antiviral activity properties by modulating lipid metabolism and various signaling pathways. However, the specific role of CH25H in regulating NDV infection and replication remains unclear. In this study, we demonstrate that CH25H significantly inhibits NDV replication by blocking viral entry through its enzymatic product, 25HC. Notably, a catalytic mutant of CH25H (CH25H-M), which lacks hydroxylase activity, still retains partial ability to inhibit NDV replication, suggesting the involvement of an enzyme-independent antiviral mechanism. Furthermore, we found that CH25H interacts with the viral nucleoprotein (NP), leading to a reduction in NP expression and inhibition of viral ribonucleoprotein (RNP) complex activity. These findings reveal that CH25H exerts antiviral effects through both enzyme-dependent and -independent mechanisms, providing new insights into its role in host defense and offering potential targets for the development of antiviral therapies.IMPORTANCECholesterol 25-hydroxylase (CH25H) is a multifunctional host protein that has been implicated in regulating the life cycles of various viruses. As a prototype of paramyxovirus, Newcastle disease virus (NDV) poses a significant threat to the global poultry industry, causing substantial economic losses. Uncovering the mechanisms of NDV-host interactions is crucial for unraveling the viral pathogenesis and the host immune response, which can drive the development of effective antiviral therapies. Here, we demonstrate that CH25H, whose expression is induced upon NDV infection, plays a pivotal role in restricting viral replication. Specifically, CH25H interacts with the viral NP and inhibits the viral RNP activity. These findings expand our understanding of CH25H's antiviral functions and offer new insights into virus-host interactions, providing potential targets for the development of novel antiviral drugs against NDV and related pathogens.

Keywords:  25-hydroxycholesterol; Newcastle disease virus; cholesterol 25-hydroxylase; viral replication

DOI:  https://doi.org/10.1128/jvi.00428-25
Immunology. 2025 Apr 23.

Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.

Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Larissa Menezes Dos Reis, Isabella Bonilha de Oliveira, José Luís Fachi, João Victor Virgilio-da-Silva, Marcelo Rodrigues Berçot, Mariane Font Fernandes, Sarah de Oliveira, Nathalia Vitoria Pereira Araujo, Guilherme Ribeiro, Gisele de Castro, Webster Leonardo Guimarães Costa, Adriana Leandra Santoro, Gabriela Flavia Rodrigues-Luiz, Helison Rafael P do Carmo, Ikaro Breder, Marcelo A Mori, Alessandro S Farias, Daniel Martins-de-Souza, Joseph W Guarnieri, Douglas C Wallace, Marco Aurélio Ramirez Vinolo, José Luiz Proença-Módena, Afshin Beheshti, Andrei C Sposito, Pedro M Moraes-Vieira.

  Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA-derived acetyl-CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL-6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID-19.

Keywords:  COVID‐19; inflammation; innate immunity; monocyte; obesity

DOI:  https://doi.org/10.1111/imm.13934
Pestic Biochem Physiol. 2025 May;pii: S0048-3575(25)00101-4. [Epub ahead of print]210 106388

Bombyx mori nuclear polyhedrosis virus infection regulated by host glycosphingolipids.

Feifei Zhu, Jindie Hong, Tingting Xue, Qi Tang, Qian Yu, Guohui Li, Shangshang Ma, Xiaoyong Liu, Shuhao Huo, Keping Chen.

  Glycosylation is an important post-translational modification commonly found in eukaryotes, and plays crucial roles in many biological activities. The silkworm Bombyx mori (B. mori), an important economic insect and a model organism in biology, has recently been found to be abundantly glycosylated. In this study, we established the role of silkworm glycosphingolipids (GSLs), the glycoconjugates formed by covalent attachment of a glycan to the lipid class of ceramide, during B. mori nuclear polyhedrosis virus (BmNPV) infection. The levels of cellular glycosphingolipids (GSLs), particularly the glucosylceramide (Glc-Cer) series, were modulated by targeting uridine diphosphate-glucose ceramide glycosyltransferase (UGCG), the enzyme responsible for Glc-Cer synthesis. Inhibiting UGCG activity by Genz-123346 (Genz), an inhibitor and substrate analogue of UGCG, reduced BmNPV binding, internalization, and viral protein expression in BmN cells. A general reduction in the cellular GSL contents was observed following Genz treatment. Overexpression of UGCG increased cellular GSL levels overall while still caused suppression in viral infection. It is postulated that GSLs are highly regulated membrane components that are crucial for viral entry, and disturbing the balance, either by increasing or decreasing cellular GSL components, alters membrane traffic and transport, which is unfavorable for viral infection. Therefore, highly regulated cellular GSLs are required for effective BmNPV infection. This study provides direct evidence linking GSL levels to BmNPV infection, offering new insights into the role of GSLs in viral infection.

Keywords:  BmNPV; Glycosphingolipid; Silkworm; UDP-glucosylceramide glycosyltransferase

DOI:  https://doi.org/10.1016/j.pestbp.2025.106388
Front Pharmacol. 2025 ;16 1564504

Antiviral activity of eicosapentaenoic acid against zika virus and other enveloped viruses.

Yifei Feng, Shuqi Qiu, Shuting Zou, Ru Li, Hongyu Chen, Kaitian Chen, Junbo Ma, Jinyu Liu, Xiaoyun Lai, Shuwen Liu, Min Zou.

   Background: Zika virus (ZIKV) is an emerging flavivirus that may cause innate microcephaly or neurological disturbances. Yet no antiviral has been approved by FDA against ZIKV infection. It was shown that some unsaturated fatty acids could inactivate enveloped viruses including SARS-CoV-2. However, studies investigating the effect of eicosapentaenoic acid (EPA) on ZIKV infection are lacking. This study aims to evaluate the antiviral effect of EPA against ZIKV and other enveloped viruses.
Methods: We first explored the toxicities of EPA in vitro and in vivo. Then we examined the antiviral effect of EPA against ZIKV via cell-based immunodetection, qRT-PCR, Western blotting, and so on. To uncover its antiviral mechanism, we performed assays for virus binding, adsorption and entry, and time-of-addition. RNase digestion and ZIKV NS2B-NS3 protease inhibition assays were also adopted. Finally, we detected its effects on dengue virus (DENV)-2, herpes simplex virus (HSV)-1 and influenza A virus via MTT, Western blotting and qRT-PCR assays.
Results: EPA was found to inhibit ZIKV infection in vitro without causing cytotoxicities. EPA exhibited antiviral activity in the early stages of the ZIKV life cycle quickly. Mechanistic experiments showed that EPA disrupted the membrane integrity of viral particles, leading to the release of viral RNA, together with the interruption of ZIKV from binding, adsorption and entry, and ultimately the inhibition of viral proliferation. Furthermore, EPA exerted antiviral effects against DENV-2, HSV-1, and influenza virus, in a dose-dependent manner.
Conclusion: These findings suggest that EPA is a promising broad-spectrum antiviral drug candidate.

Keywords:  EPA; ZIKV; adsorption; antiviral activity; binding; entry

DOI:  https://doi.org/10.3389/fphar.2025.1564504
Nat Commun. 2025 Apr 24. 16(1): 3874

IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.

Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur.

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an anti-tumor immune response which is important for viral efficacy. Mutant IDH (IDHR132H) gliomas are incapable of reductive carboxylation and hence ferroptosis. Pharmacological blockade of IDHR132H induces ferroptosis and anti-tumor immunity. This study provides a rationale to use an IDHR132H inhibitor to treat high grade IDH-mutant glioma patients undergoing oHSV treatment.

DOI: https://doi.org/10.1038/s41467-025-58911-2