bims-mevinf 2025-01-19 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–01–19
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.
Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.
Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation.
Non-Structural Protein V of Canine Distemper Virus Induces Autophagy via PI3K/AKT/mTOR Pathway to Facilitate Viral Replication.
SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy.
Proteomic and metabolomic profiling of plasma uncovers immune responses in patients with Long COVID-19.
NRF2 Antioxidant Response and Interferon-Stimulated Genes Are Differentially Expressed in SARS-CoV-2-Positive Young Subjects.

J Virol. 2025 Jan 16. e0211024

Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.

Lara Dsouza, Anil Pant, Blake Pope, Zhilong Yang.

  The molecular mechanisms by which vaccinia virus (VACV), the prototypical member of the poxviridae family, reprograms host cell metabolism remain largely unexplored. Additionally, cells sense and respond to fluctuating nutrient availability, thereby modulating metabolic pathways to ensure cellular homeostasis. Understanding how VACV modulates metabolic pathways in response to nutrient signals is crucial for understanding viral replication mechanisms, with the potential for developing antiviral therapies. In this study, we establish the importance of de novo pyrimidine synthesis during VACV infection. We report the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor (EGF), in enabling VACV to phosphorylate the key enzyme CAD of the de novo pyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. Although nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via the mTORC1-S6K1 signaling axis in a VGF-dependent manner, especially upon glutamine and asparagine limitation. However, unlike its cellular homolog EGF, the VGF peptide alone, in the absence of VACV infection, has minimal ability to activate CAD. This suggests the involvement of other viral factors yet to be identified. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, de novo pyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector.IMPORTANCEViruses often reprogram host cell metabolism to facilitate replication. How poxviruses, such as the prototype member, vaccinia virus (VACV), modulate host cell metabolism is not well understood. Understanding how VACV affects these metabolic pathways is key to learning about viral replication and developing antiviral treatments. This study highlights the importance of de novo pyrimidine synthesis during VACV infection. We found that the vaccinia growth factor (VGF), a viral protein similar to the cellular epidermal growth factor (EGF), helps VACV activate the enzyme CAD of the de novo pyrimidine pathway. Upon nutrient limitation, VGF is needed for the activation of CAD through mTORC1-S6K signaling. VGF peptide alone is unable to activate this pathway independent of infection, suggesting the involvement of other viral factor(s). Our research not only sheds light on how VACV regulates metabolism but also holds promise for improving VACV as a cancer treatment and vaccine.

Keywords:  CAD; asparagine; glutamine; mTORC1; metabolism; nutrient stress; nutrition; poxvirus; pyrimidine; vaccinia virus

DOI:  https://doi.org/10.1128/jvi.02110-24
PLoS Pathog. 2025 Jan 13. 21(1): e1012872

Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.

Zhe Sun, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, Juan Bai, Jiang Pi, Ping Jiang, Xing Liu.

Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.

DOI: https://doi.org/10.1371/journal.ppat.1012872
JHEP Rep. 2025 Jan;7(1): 101225

Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation.

Masahiko Ito, Jie Liu, Masayoshi Fukasawa, Koji Tsutsumi, Yumi Kanegae, Mitsutoshi Setou, Michinori Kohara, Tetsuro Suzuki.

   Background & Aims: Hepatic steatosis, characterized by lipid accumulation in hepatocytes, is a key diagnostic feature in patients with chronic hepatitis C virus (HCV) infection. This study aimed to clarify the involvement of phospholipid metabolic pathways in the pathogenesis of HCV-induced steatosis.
Methods: The expression and distribution of lipid species in the livers of human liver chimeric mice were analyzed using imaging mass spectrometry. Triglyceride accumulation and lipid droplet formation were studied in phospholipase A2 group 4C (PLA2G4C) knockout or overexpressing cells.
Results: Imaging mass spectrometry of the infected mouse model revealed increased lysophosphatidylcholine levels and decreased phosphatidylcholine levels in HCV-positive regions of the liver. Among the transcripts associated with phosphatidylcholine biosynthesis, upregulation of PLA2G4C mRNA was most pronounced following HCV infection. Activation of the transcription factor NF-κB and upregulation of c-Myc were important for activation of PLA2G4C transcription by HCV infection and expression of the viral proteins Core-NS2. The amount and size of lipid droplets were reduced in PLA2G4C-knockout cells. Inhibition of NF-κB or c-Myc activity suppressed lipid droplet formation in HCV-infected cells. HCV infection promoted the stabilization of lipid droplets, but this stability was reduced in PLA2G4C-knockout cells. Overexpression of PLA2G4C decreased the levels of phosphatidylcholine species in the lipid droplet fraction and led to lower levels of key factors involved in lipolysis (breakdown of triglycerides into glycerol and free fatty acids), such as ATGL, PLIN1 and ABHD5 on the lipid droplets.
Conclusions: HCV infection markedly increases PLA2G4C expression. This may alter the phospholipid composition of the lipid droplet membrane, leading to stabilization and enlargement of the droplets.
Impact and implications: The involvement of phospholipid metabolism pathways in the pathogenesis of hepatitis C virus (HCV)-related liver diseases remains unclear. We found that PLA2G4C expression is upregulated through NF-κB and c-Myc activation upon HCV infection, and this upregulation is associated with a decrease in phosphatidylcholine species. The increased expression of PLA2G4C resulted in changes in the phospholipid composition of lipid droplets, led to the dissociation of lipolysis-related factors from the lipid droplet surface and the accumulation of lipid content within the droplets. These findings suggest that the disruption of the phospholipid metabolism pathway caused by HCV infection may contribute to the development of HCV-associated fatty liver. It would be interesting to determine whether alcohol- and/or metabolic dysfunction-associated steatohepatitis are also associated with increased PLA2 activity, altered phospholipid composition and decreased levels of ATGL and its cofactors in lipid droplet membranes.

Keywords:  HCV; PLA2G4C; human hepatocyte chimeric mice; lipidome analysis; liver steatosis

DOI:  https://doi.org/10.1016/j.jhepr.2024.101225
Int J Mol Sci. 2024 Dec 25. pii: 84. [Epub ahead of print]26(1):

Non-Structural Protein V of Canine Distemper Virus Induces Autophagy via PI3K/AKT/mTOR Pathway to Facilitate Viral Replication.

Xin Tian, Rui Zhang, Shuang Yi, Yu Chen, Ying Jiang, Xianwen Zhang, Zhidong Zhang, Yanmin Li.

  Canine distemper (CD) is a highly infectious disease of dogs which is caused by canine distemper virus (CDV). Previous studies have demonstrated that CDV infection can induce autophagy in cells. However, the mechanism underlying CDV-induced autophagy remains not fully understood. The CDV non-structural protein V plays a vital role in viral replication and pathogenicity in the host. In this study, we investigated the relationship between the CDV-V protein and autophagy induction and further explored its impact on the viral replication and the mechanism behind this. Our results showed that the V protein induced autophagy via inhibiting the phosphorylation of PI3K, AKT, and mTOR to promote viral replication. The activation or inhibition of PI3K phosphorylation resulted in enhancing or reducing viral replication, respectively. Further studies revealed that the V protein interacted with PI3K to induce cellular autophagy. The present study demonstrated that the CDV-V protein can induce cellular autophagy by inhibiting the PI3K/AKT signaling pathway to enhance viral replication. The results improve the understanding of the molecular mechanism of CDV infection and offer new perspectives for the development of effective treatment and prevention strategies.

Keywords:  CDV-V; PI3K; autophagy; canine distemper virus (CDV)

DOI:  https://doi.org/10.3390/ijms26010084
EBioMedicine. 2025 Jan 13. pii: S2352-3964(24)00569-3. [Epub ahead of print]112 105533

SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy.

Qi-Sheng Zhang, Jia-Ning Wang, Tian-Ling Yang, Si-Yao Li, Jia-Qi Li, Ding-Ning Liu, Hong Shang, Zi-Ning Zhang.

   BACKGROUND: Although antiretroviral therapy (ART) effectively inhibits viral replication, it does not fully mitigate the immunosenescence instigated by HIV infection. Cellular metabolism regulates cellular differentiation, survival, and senescence. Serine hydroxymethyltransferase 2 (SHMT2) is the first key enzyme for the entry of serine into the mitochondria from the de novo synthesis pathway that orchestrates its conversion glutathione (GSH), a key molecule in neutralising ROS and ensuring the stability of the immune system. It remains incompletely understood whether SHMT2 is involved in the senescence of CD8+ T cells, crucial for immune vigilance against HIV.
METHODS: HIV-infected individuals receiving antiretroviral therapy were enrolled in our study. SHMT2-siRNA was electroporated into T cells to disrupt the gene expression of SHMT2, followed by the quantification of mRNA levels of crucial serine metabolism enzymes using real-time PCR. Immunophenotyping, proliferation, cellular and mitochondrial function, and senescence-associated signalling pathways were examined using flow cytometry in CD8+ T cell subsets.
FINDINGS: Our findings revealed that CD8+ T cells in HIV-infected subjects are inclined towards senescence, and we identified that SHMT2, a key enzyme in serine metabolism, plays a role in CD8+ T cell senescence. SHMT2 can regulate glutathione (GSH) synthesis and protect mitochondrial function, thus effectively controlling intracellular reactive oxygen species (ROS) levels. Moreover, SHMT2 significantly contributes to averting immunosenescence and sustaining CD8+ T cell competence by modulating downstream DNA damage and phosphorylation cascades in pathways intricately linked to cellular senescence. Additionally, our study identified glycine can ameliorate CD8+ T cell senescence in HIV-infected individuals.
INTERPRETATION: Decreased SHMT2 levels in HIV-infected CD8+ T cells affect ROS levels by altering mitochondrial function and GSH content. Increased ROS levels activate senescence-related signalling pathways in the nucleus. However, glycine supplementation counteracts these effects and moderates senescence.
FUNDING: This study was supported by grants from the National Key R&D Program of China (2021YFC2301900-2021YFC2301901), National Natural Science Foundation of China (82372240), and Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2022JH2/20200074).

Keywords:  Antiretroviral therapy (ART); Human immunodeficiency virus (HIV); SHMT2; Senescence

DOI:  https://doi.org/10.1016/j.ebiom.2024.105533
Front Microbiol. 2024 ;15 1470193

Proteomic and metabolomic profiling of plasma uncovers immune responses in patients with Long COVID-19.

Yulin Wei, Hongyan Gu, Jun Ma, Xiaojuan Mao, Bing Wang, Weiyan Wu, Shiming Yu, Jinyuan Wang, Huan Zhao, Yanbin He.

  Long COVID is an often-debilitating condition with severe, multisystem symptoms that can persist for weeks or months and increase the risk of various diseases. Currently, there is a lack of diagnostic tools for Long COVID in clinical practice. Therefore, this study utilizes plasma proteomics and metabolomics technologies to understand the molecular profile and pathophysiological mechanisms of Long COVID, providing clinical evidence for the development of potential biomarkers. This study included three age- and gender-matched cohorts: healthy controls (n = 18), COVID-19 recovered patients (n = 17), and Long COVID patients (n = 15). The proteomics results revealed significant differences in proteins between Long COVID-19 patients and COVID-19 recovered patients, with dysregulation mainly focused on pathways such as coagulation, platelets, complement cascade reactions, GPCR cell signal transduction, and substance transport, which can participate in regulating immune responses, inflammation, and tissue vascular repair. Metabolomics results showed that Long COVID patients and COVID-19 recovered patients have similar metabolic disorders, mainly involving dysregulation in lipid metabolites and fatty acid metabolism, such as glycerophospholipids, sphingolipid metabolism, and arachidonic acid metabolism processes. In summary, our study results indicate significant protein dysregulation and metabolic abnormalities in the plasma of Long COVID patients, leading to coagulation dysfunction, impaired energy metabolism, and chronic immune dysregulation, which are more pronounced than in COVID-19 recovered patients.

Keywords:  Long COVID; mechanism; metabolomics; plasma; proteomics

DOI:  https://doi.org/10.3389/fmicb.2024.1470193
Immun Inflamm Dis. 2025 01;13(1): e70109

NRF2 Antioxidant Response and Interferon-Stimulated Genes Are Differentially Expressed in SARS-CoV-2-Positive Young Subjects.

Toscanelli Walter, Fracella Matteo, De Angelis Marta, Scagnolari Carolina, Sorrentino Leonardo, Piselli Elena, Marcocci Maria Elena, Midulla Fabio, Mancino Enrica, Nenna Raffaella, Petrarca Laura, Palamara Anna Teresa, Antonelli Guido, Pierangeli Alessandra, Nencioni Lucia.

   BACKGROUND: Several respiratory viruses, including Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), suppress nuclear factor-E2-related factor-2 (NRF2) antioxidant response, generating oxidative stress conditions to its advantage. NRF2 has also been reported to regulate the innate immune response through the inhibition of the interferon (IFN) pathway. However, its modulation in younger individuals and its correlation with the IFN response remain to be elucidated.
METHODS: The NRF2 and redox-related genes expression was examined in nasopharyngeal swabs from children attending the pediatric hospital for SARS-CoV-2 molecular testing. Expression levels were analyzed by stratifying the population according to the SARS-CoV-2 positivity, age, or the presence of symptoms. The results were correlated with Types I and III IFN genes and IFN-stimulated genes (ISGs).
RESULTS: We found that NRF2 expression was markedly diminished in positive patients compared to negative. Moreover, it correlated with higher expression of IFNα2 and IFNλ3, as well as ISG15 and ISG56. Interestingly, symptomatic patients with anosmia/ageusia showed pronounced expression of apurinic/apyrimidinic endonuclease1/redox factor 1 (APE1), together with Type I IFNs, ISG56, and the inflammasome component NLRP3.
CONCLUSION: The results indicate an interdependence between NRF2 antioxidant pathway and IFN-mediated response during SARS-CoV-2 infection in young subjects.

Keywords:  APE‐1; Interferon response; NRF2; SARS‐CoV‐2; antioxidant response; inflammasome

DOI:  https://doi.org/10.1002/iid3.70109