bims-mevinf 2025-03-02 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–03–02
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Feline Calicivirus Infection Manipulates Central Carbon Metabolism.
STEAP3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Regulating Fatty Acid and Lipid Droplet Synthesis.
Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus.
Porcine reproductive and respiratory syndrome virus nsp5 inhibits the activation of the Nrf2/HO-1 pathway by targeting p62 to antagonize its antiviral activity.
Severe acute respiratory syndrome coronavirus 2 infection unevenly impacts metabolism in the coronal periphery of the lungs.
NAD+ Suppresses EV-D68 Infection by Enhancing Anti-Viral Effect of SIRT1.
Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis.
Assessment of Oxidative Stress Parameters in Iraqi Male Patients with Covid-19; A Case Control Study.
Seneca Valley virus infection exploits DNA damage response to facilitate viral replication.
Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19.
Wheat Yellow Mosaic Virus P1 Inhibits ROS Accumulation to Facilitate Viral Infection.

Vet Sci. 2025 Feb 07. pii: 138. [Epub ahead of print]12(2):

Feline Calicivirus Infection Manipulates Central Carbon Metabolism.

Guangrong Zhao, Hongwei Zhu, Xiu Xue, Chenpei Zhao, Xin Yu, Linlin Jiang, Jingxian Cong, Yang Liu, Yuanlong He, Jianlong Zhang, Xingxiao Zhang.

  Viruses can manipulate the host metabolism to achieve optimal replication conditions, and central carbon metabolism (CCM) pathways are often crucial in determining viral infections. Feline calicivirus (FCV), a diminutive RNA viral agent, induces upper respiratory tract infections in feline hosts, with highly pathogenic strains capable of precipitating systemic infections and subsequent host cell necrosis, thereby presenting a formidable challenge to feline survival and protection. However, the relationship between FCV and host cell central carbon metabolism (CCM) remains unclear, and the precise pathogenic mechanisms of FCV are yet to be elucidated. Upon FCV infection of Crandell-Rees Feline Kidney (CRFK) cells, an enhanced cellular uptake of glucose and glutamine was observed. Metabolomics analyses disclosed pronounced alterations in the central carbon metabolism of the infected cells. FCV infection was found to augment glycolytic activity while sustaining the tricarboxylic acid (TCA) cycle flux, with cellular ATP levels remaining invariant. Concurrently, both glutamine metabolism and the flux of the pentose phosphate pathway (PPP) were noted to be intensified. The application of various inhibitory agents targeting glycolysis, glutamine metabolism, and the PPP resulted in a significant suppression of FCV proliferation. Experiments involving glucose and glutamine deprivation demonstrated that the absence of either nutrient markedly curtailed FCV replication. Collectively, these findings suggest a critical interplay between central carbon metabolism and FCV proliferation. FCV infection stimulates CRFK cells to augment glucose and glutamine uptake, thereby supplying the necessary metabolic substrates and energy for viral replication. During the infection, glutamine emerges as the primary energy substrate, ensuring ATP production and energy homeostasis, while glucose is predominantly channeled into the pentose phosphate pathway to facilitate nucleotide synthesis.

Keywords:  glutamine metabolism; glycolysis; metabolomics; pentose phosphate pathway

DOI:  https://doi.org/10.3390/vetsci12020138
Vet Sci. 2025 Feb 08. pii: 147. [Epub ahead of print]12(2):

STEAP3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Regulating Fatty Acid and Lipid Droplet Synthesis.

Chenyang Yuan, Kaifeng Guan, Gaiping Zhang.

  Porcine Reproductive and Respiratory Syndrome (PRRS) is a contagious disease that impacts swine health worldwide. Lipid metabolism plays a vital role in energy production and is regulated by various genes involved in lipogenesis and lipolysis. In this study, we found that PRRSV infection significantly reduced the protein expression of STEAP3. The overexpression of STEAP3 can notably inhibit PRRSV replication. Additionally, we utilized transcriptomics and metabolomics to examine the effects of STEAP3 on PRRSV replication, identifying important pathways associated with energy metabolism and lipogenesis. We subsequently found that STEAP3 can suppress PRRSV replication by regulating fatty acid synthesis and enhancing lipid droplet formation. Overall, these findings indicate that STEAP3 could be a potential target for developing strategies to manage PRRSV infection by modulating lipid metabolism.

Keywords:  PRRSV; STEAP3; lipogenesis; metabolomics; transcriptomics

DOI:  https://doi.org/10.3390/vetsci12020147
Pathogens. 2025 Feb 02. pii: 132. [Epub ahead of print]14(2):

Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus.

Yumi Jang, Fred Bunz.

  The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5, but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by co-opting IRE1α and suppressing XBP1s. Our findings illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

Keywords:  XBP1 splicing; adenovirus; p53; unfolded protein response

DOI:  https://doi.org/10.3390/pathogens14020132
J Virol. 2025 Feb 28. e0158524

Porcine reproductive and respiratory syndrome virus nsp5 inhibits the activation of the Nrf2/HO-1 pathway by targeting p62 to antagonize its antiviral activity.

Fang Wang, Fructueux Modeste Amona, Yipeng Pang, Qiaoya Zhang, Yuan Liang, Xiaohan Chen, Yongding Ke, Junhao Chen, Chengchuang Song, Yanhong Wang, Zongyun Li, Chunlei Zhang, Xingtang Fang, Xi Chen.

  Porcine reproductive and respiratory syndrome virus (PRRSV) infections often trigger oxidative stress and cytokine storms, resulting in significant tissue damage that causes fatalities in piglets and reproductive issues in sows. However, it is still unknown how oxidative stress is regulated by viral and host factors in response to PRRSV infection. Here, we found that PRRSV induced cellular oxidative stress by triggering the production of reactive oxygen species and inhibiting the expression of antioxidant enzymes. Although Nrf2 is an important redox regulator that initiates the expression of downstream antioxidant genes, PRRSV can impair the Nrf2/HO-1 pathway. The overexpression of Nrf2 showed a significant anti-PRRSV effect, and inhibiting the expression of Nrf2 promoted the proliferation of PRRSV. Further analysis showed that Nrf2 positively regulated the production of type I interferons and interferon-stimulated genes, which may contribute to its anti-PRRSV effect. By screening the PRRSV-encoded protein, we found that the PRRSV nsp5 protein can degrade Nrf2 at the protein level. Mechanistically, nsp5 promotes Nrf2-Keap1 binding affinity by inhibiting p62-mediated Keap1 sequestration and increasing Keap1 expression. Subsequently, this increased Keap1-mediated degradation of Nrf2 ubiquitination through K48-linked polyubiquitin. Furthermore, we found that the residues Tyr146 and Arg147 of nsp5 are crucial for inhibiting the activation of the p62-mediated Nrf2 antioxidant pathway. Thus, our findings uncover a novel mechanism by which PRRSV disrupts the host antioxidant defense system and highlight the crucial role of the Nrf2/HO-1 antioxidant pathway in host defense against PRRSV.IMPORTANCEOxidative stress-induced redox imbalance is a crucial pathogenic mechanism in viral infections. Nrf2 and its antioxidant genes serve as the main defense pathways against oxidative stress. However, the role of Nrf2 in the context of porcine reproductive and respiratory syndrome virus (PRRSV) infection remains unclear. In this study, we demonstrated that PRRSV infection decreased the expression of antioxidant genes of the Nrf2 signaling pathway and overexpression of Nrf2 triggered a strong anti-PRRSV effect. PRRSV nsp5 enhanced Keap1-dependent degradation of Nrf2 ubiquitination, thereby weakening cellular resistance to oxidative stress and antagonizing the antiviral activity of Nrf2. Our study further revealed a new mechanism by which PRRSV evades host antiviral innate immunity by disturbing cellular redox homeostasis, providing a new target for developing anti-PRRSV drugs.

Keywords:  Keap1; Nrf2/HO-1; PRRSV; nsp5; oxidative stress; p62

DOI:  https://doi.org/10.1128/jvi.01585-24
iScience. 2025 Feb 21. 28(2): 111727

Severe acute respiratory syndrome coronavirus 2 infection unevenly impacts metabolism in the coronal periphery of the lungs.

Jarrod Laro, Biyun Xue, Jian Zheng, Monica Ness, Stanley Perlman, Laura-Isobel McCall.

  SARS-CoV-2, the virus responsible for COVID-19, is a highly contagious virus that can lead to hospitalization and death. COVID-19 is characterized by its involvement in the lungs, particularly the lower lobes. To improve patient outcomes and treatment options, a better understanding of how SARS-CoV-2 impacts the body, particularly the lower respiratory system, is required. In this study, we sought to understand the spatial impact of COVID-19 on the lungs of mice infected with mouse-adapted SARS2-N501YMA30. Overall, infection caused a decrease in fatty acids, amino acids, and most eicosanoids. When analyzed by segment, viral loads were highest in central lung tissue, while metabolic disturbance was highest in peripheral tissue. Infected peripheral lung tissue was characterized by lower levels of fatty acids and amino acids when compared to central lung tissue. This study highlights the spatial impacts of SARS-CoV-2 and helps explain why peripheral lung tissue is most damaged by COVID-19.

Keywords:  Human metabolism; Immunology

DOI:  https://doi.org/10.1016/j.isci.2024.111727
Viruses. 2025 Jan 26. pii: 175. [Epub ahead of print]17(2):

NAD+ Suppresses EV-D68 Infection by Enhancing Anti-Viral Effect of SIRT1.

Yue Wang, Haiyu Li, Xia Huang, Yan Huang, Mingqi Lv, Hong Tang, Xinyue Han, Juntong Liu, Yan Liang, Guangchao Zang, Nan Lu, Guangyuan Zhang.

  Enterovirus 68 (EV-D68) is a non-enveloped virus with a positive-sense single-stranded RNA genome that causes respiratory diseases and acute flaccid myelitis, posing significant threats to human health. However, an effective vaccine remains undeveloped. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent enzyme, plays a key role in cellular metabolism, but its interaction with NAD+ during viral infections is not well understood. In this study, through a metabolomics analysis, we demonstrate that EV-D68 infection influences cellular metabolism. Additionally, we show that NAD+ inhibits EV-D68 infection both in vivo and in vitro. EV-D68 reduces cellular NAD+ levels by regulating the expression of enzymes involved in NAD+ consumption and synthesis. Moreover, the infection increases the expression of sirtuin 1 (SIRT1), which inhibits EV-D68 replication in turn. Mechanistically, SIRT1 suppresses EV-D68 5'UTR-mediated translation, and the antiviral effect of SIRT1 on EV-D68 replication is enhanced by NAD+. Collectively, our findings highlight the critical role of NAD+ metabolism in EV-D68 infection and reveal the antiviral potential of SIRT1, providing valuable insights for the development of antiviral strategies.

Keywords:  EV-D68; NAD+; SIRT1; metabolism; replication

DOI:  https://doi.org/10.3390/v17020175
Sci Rep. 2025 Feb 24. 15(1): 6622

Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis.

Iana V Russkikh, Oleg S Popov, Tatiana G Klochkova, Natalia N Sushentseva, Svetlana V Apalko, Anna Yu Asinovskaya, Sergey V Mosenko, Andrey M Sarana, Sergey G Shcherbak.

  The clinical manifestations of the cytokine storm (CS) associated with COVID-19 resemble the acute phase of sepsis. Metabolomics may contribute to understanding the specific pathobiology of these two syndromes. The aim of this study was to compare serum metabolomic profiles in CS associated with COVID-19 vs. septic surgery patients. In a retrospective cross-sectional study, serum samples from patients with CS associated with COVID-19, with and without comorbidity, as well as serum samples from patients with surgical sepsis were investigated. Targeted metabolomic analysis was performed on all samples using LC-MS/MS. Analysis revealed that similar alterations in the serum metabolome of patients with COVID-19 and surgical septic patients were associated with amino acid metabolism, nitrogen metabolism, inflammatory status, methionine cycle and glycolysis. The most significant difference was found for serum levels of metabolites of kynurenine synthesis, tricarboxylic acid cycle, gamma-aminobutyric acid and niacinamide. The metabolic pathway of cysteine and methionine metabolism was significantly disturbed in COVID-19 and surgical septic patients. For the first time, the similarities and differences between the serum metabolomic profiles of patients with CS associated with COVID-19 and patients with surgical sepsis were investigated for patients from the Northwest of the Russian Federation.

Keywords:  COVID-19; Cytokine storm; LC–MS/MS; Metabolic pathways; Sepsis; Targeted metabolomic analysis

DOI:  https://doi.org/10.1038/s41598-025-90426-0
Rep Biochem Mol Biol. 2024 Jul;13(2): 167-173

Assessment of Oxidative Stress Parameters in Iraqi Male Patients with Covid-19; A Case Control Study.

Zainab Nazar Hasan Anber, Basil Oied Saleh, Riyadh Hassan Majed.

   Background: SARS-CoV-2 infection can cause significant alterations in our lives. Oxidative stress (OS) has been proposed to play a major role in COVID-19 pathogenesis, and the determination of OS biomarkers provides insight into disease severity.
Methods: The study was conducted during the second wave of the pandemic in 2020. Fifty blood samples were collected from patients admitted to one of the COVID-19 isolation centers in Baghdad, Iraq. The samples were subdivided into 25 patients admitted to the intensive care unit (ICU) and 25 non-ICU patients, compared to 25 healthy controls. All participants were aged 35-52 years.
Results: The study showed that the mean (±SD) serum total oxidant status (TOS) and malondialdehyde (MDA) levels were significantly increased (p< 0.001) in the ICU group compared to the control and non-ICU groups. Conversely, the levels of serum total antioxidant capacity (TAC) and serum antioxidative enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase, and glutathione (GSH) were significantly decreased (p< 0.001) in the ICU group compared to both the control and non-ICU groups. Serum zinc levels were significantly decreased (p< 0.001) in both ICU and non-ICU groups compared to the control group, while serum selenium (Se), copper (Cu), and vitamins C and E were significantly decreased (p< 0.001) in the ICU group compared to both the control and non-ICU groups.
Conclusions: The presence of OS biomarkers in the sera of COVID-19 patients offers a potential new approach for the treatment of this disease.

Keywords:  Antioxidants; COVID-19; Oxidants; Oxidative stress

DOI:  https://doi.org/10.61186/rbmb.13.2.167
J Virol. 2025 Feb 26. e0221124

Seneca Valley virus infection exploits DNA damage response to facilitate viral replication.

Jiangwei Song, Zijian Li, Jingjing Yang, Ruiyi Ma, Dan Wang, Rong Quan, Xuexia Wen, Jue Liu.

  Seneca Valley virus (SVV) is an emerging pathogen that causes severe vesicular diseases in swine, posing a significant threat to the global pork industry. DNA and RNA viruses manipulate the host DNA damage response (DDR) to modulate cellular machinery and facilitate their life cycles. However, the interaction between the host DDR and SVV infection remains unexplored. Here, we aimed to comprehensively investigate the DDR and DNA repair signaling pathways during SVV infection. We found that SVV infection causes DNA damage and triggers distinct DDR signaling pathways, including ataxia telangiectasia-mutated (ATM) kinase, ATM-Rad3-related kinase, and DNA-dependent protein kinase. However, it failed to induce the formation of γH2AX and 53BP1 foci, resulting in unrepaired DNA damage. Furthermore, we found that SVV 2B and 2C proteins can activate DDR signaling pathways and impair DNA repair. SVV-induced DDR triggered NF-κB signaling accompanied by upregulation of pro-inflammatory cytokines, as evidenced by the inhibition of ATM kinase, abolished SVV-induced NF-κB activation. Inhibition of the ATM pathway attenuated SVV replication. These findings expand our understanding of host DDR manipulation during viral infection and provide crucial insights into a novel mechanism exploited by SVV to regulate the inflammatory response for efficient replication.IMPORTANCEDDR is a cellular machinery that senses and repairs host DNA lesions to maintain genome integrity. Viruses have evolved diverse strategies to manipulate host DDR for replicative efficiency. SVV is an emerging virus that causes vesicular diseases in pigs and severely threatens the swine industry. However, the interaction between SVV and DDR remains unclear. Here, we found that SVV modulates host DDR pathways to facilitate viral replication. Our results demonstrated that SVV infection causes DNA damage, activates ATM-mediated DNA double-strand break response, and impedes DNA repair. SVV 2B and 2C proteins induced DNA damage and activated the DDR pathway while impairing repair mechanisms. This study revealed a fine-tuned molecular mechanism of SVV-modulated DDR that contributes to viral replication, facilitating deeper insight into SVV replication.

Keywords:  DNA damage response (DDR); DNA double-strand break (DSB); DNA repair; Seneca Valley virus (SVV); viral replication

DOI:  https://doi.org/10.1128/jvi.02211-24
Cells. 2025 Feb 11. pii: 256. [Epub ahead of print]14(4):

Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19.

Liqing He, Yunke Wang, Fang Yuan, Samantha Morrissey, Anne E Geller, Xiaoling Hu, Raobo Xu, Xipeng Ma, Huang-Ge Zhang, Kenneth McLeish, Jiapeng Huang, Xiang Zhang, Jun Yan.

  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma (n = 61) and paired bronchoalveolar lavage fluid (BALF) samples (n = 20) using parallel two-dimensional liquid chromatography-mass spectrometry (2DLC-MS). In addition, we studied how an identified metabolite regulates the immunopathogenesis of COVID-19. The results unveiled distinct metabolome changes between healthy donors, and moderate and severe patients in both plasma and BALF, indicating that locations and disease severity play critical roles in COVID-19 metabolic alteration. Notably, a vital metabolite, indoxyl sulfate, was found to be elevated in both the plasma and BALF of severe COVID-19 patients. Indoxyl sulfate selectively induced TNF-α production, reduced co-stimulatory signals, and enhanced apoptosis in human monocytes. Moreover, its levels negatively correlated with the strength of co-stimulatory signals and antigen presentation capability in monocytes of COVID-19 patients. Collectively, our findings suggest that the levels of indoxyl sulfate could potentially serve as a functional biomarker to monitor COVID-19 disease progression and guide more individualized treatment for COVID-19 patients.

Keywords:  COVID-19; immune regulation; indoxyl sulfate; metabolism; monocytes

DOI:  https://doi.org/10.3390/cells14040256
Int J Mol Sci. 2025 Feb 10. pii: 1455. [Epub ahead of print]26(4):

Wheat Yellow Mosaic Virus P1 Inhibits ROS Accumulation to Facilitate Viral Infection.

Yingjie Zhao, Jiaqian Yang, Ying Liu, Xiaodi Hu, Xia Wang, Jian Yang, Jiaqian Liu.

  Reactive oxygen species (ROS), as signaling molecules, play a crucial role in the plant immune response. However, the mechanism(s) by which viruses affect ROS metabolism remain largely unexplored. Here, we found that wheat yellow mosaic virus (WYMV)-encoded P1 is a pathogenic protein. Transcriptomic and proteomic integrative analyses were performed on WYMV-infected overexpressing-P1 wheat and wild-type plants. A total of 9245 differentially expressed genes (DEGs) and 1383 differentially expressed proteins (DEPs) were identified in the transcriptome and proteome, respectively. At their intersection, 373 DEGs/Ps were identified. Enrichment analysis revealed that the expression of genes related to the ROS metabolism pathway in overexpressed P1 transgenic wheat (OE-P1) plants significantly increased during WYMV infection. We screened peroxidase (TaPOD) and thioredoxin reductase (TaTrxR) as they showed the most significant differences in expression. The silencing of TaPOD and TaTrxR revealed that they positively regulate WYMV infection by reducing ROS accumulation. Furthermore, hydrogen peroxide treatment induced WYMV resistance in wild-type wheat plants and OE-P1 transgenic plants. This study provides a theoretical basis for the role of P1 in plant viral infection.

Keywords:  BSMV-VIGS; RNA-seq and LC-MS/MS; ROS scavenging; WYMV-P1

DOI:  https://doi.org/10.3390/ijms26041455