bims-mevinf 2024-12-29 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–12–29
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.
Targeting host integrated stress response: lead discovery of flavonoid compounds active against coronaviruses PEDV and PDCoV.
African swine fever virus enhances viral replication by increasing intracellular reduced glutathione levels, which suppresses stress granule formation.
Viral-host molecular interactions and metabolic modulation: Strategies to inhibit flaviviruses pathogenesis.
Nitazoxanide controls virus viability through its impact on membrane bioenergetics.
Longitudinal Metabolomics Reveals Metabolic Dysregulation Dynamics in Patients with Severe COVID-19.
Human cytomegalovirus RNA2.7 inhibits ferroptosis by upregulating ferritin and GSH via promoting ZNF395 degradation.

Trends Immunol. 2024 Dec 20. pii: S1471-4906(24)00296-5. [Epub ahead of print]

Epstein-Barr virus hijacks B cell metabolism to establish persistent infection and drive pathogenesis.

Bojana Müller-Durovic, Jessica Jäger, Glenn R Bantug, Christoph Hess.

  When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases.

Keywords:  B cells; Epstein–Barr virus; IDO1; NAD; cellular metabolism; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.it.2024.11.011
RSC Med Chem. 2024 Dec 23.

Targeting host integrated stress response: lead discovery of flavonoid compounds active against coronaviruses PEDV and PDCoV.

Liang Yi, Yishuai Wang, Jiehuang Wang, Yihan Chen, Weixue Huang, Ying Liao, Qingwen Zhang.

Viral infections trigger the integrated stress response (ISR) in eukaryotic cells that leads to the activation of eIF2α kinases, the elevation of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and thereby the shutdown of global protein synthesis that viruses rely on to replicate. Coronaviruses and other viruses have evolved various subversion mechanisms to counteract the antiviral ISR. These intricate host-virus interactions may be exploited by pharmacologically activating the host ISR for the development of host-directed antivirals (HDAs), an increasingly relevant area of research. In this study, we have discovered a new class of flavonoid-based ISR activators that exhibit potent antiviral activity against porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV). PEDV and PDCoV are animal coronaviruses of great veterinary and economic importance, for which there are currently no effective therapeutics. The mechanistic study indicated that lead compounds 1-B and 1-C inhibit PEDV and PDCoV replication via upregulating eIF2α phosphorylation and thereby downregulating global protein synthesis in host cells, suggesting they are HDA antivirals.

DOI: https://doi.org/10.1039/d4md00846d
Vet Res. 2024 Dec 20. 55(1): 172

African swine fever virus enhances viral replication by increasing intracellular reduced glutathione levels, which suppresses stress granule formation.

Han Gao, Taoming Gu, Xiaopeng Gao, Zebu Song, Jing Liu, Yi Song, Guihong Zhang, Yankuo Sun.

  African swine fever virus (ASFV) is a DNA virus that has significantly impacted the global swine industry. Currently, there are no effective therapies or vaccines against ASFV. Stress granules (SGs), known for their antiviral properties, are not induced during ASFV infection, even though reactive oxygen species (ROS) are generated. The mechanism by which ASFV regulates SGs formation remains unclear. This study demonstrates that ASFV antagonises SGs formation and increases intracellular levels of reduced glutathione (GSH) levels. The use of the GSH inhibitor BSO and the activator NAC confirmed that the ASFV-induced increase in GSH helps to suppress SGs formation and influences viral replication. Additionally, this study revealed that ASFV enhances GSH by upregulating the antioxidant transcription factor NRF2, as well as factors involved in GSH synthesis and regeneration, such as GCLC, and those related to the ferroptosis pathway, such as SLC7A11. Furthermore, the study uncovered that ASFV manipulates intracellular GSH levels by activating the mitochondrial protein AIFM1. This regulatory mechanism helps the virus inhibit the formation of intracellular SGs, thereby creating an optimal environment for viral replication. These findings provide new insights into the molecular strategies employed by ASFV.

Keywords:  African swine fever virus (ASFV); reduced glutathione (GSH); stress granules (SGs)

DOI:  https://doi.org/10.1186/s13567-024-01433-4
World J Virol. 2024 Dec 25. 13(4): 99110

Viral-host molecular interactions and metabolic modulation: Strategies to inhibit flaviviruses pathogenesis.

Zeeshan Ahmad Khan, Mukesh Kumar Yadav, Dong-Woo Lim, Hojun Kim, Jing-Hua Wang, AbuZar Ansari.

  Flaviviruses, which include globally impactful pathogens, such as West Nile virus, yellow fever virus, Zika virus, Japanese encephalitis virus, and dengue virus, contribute significantly to human infections. Despite the ongoing emergence and resurgence of flavivirus-mediated pathogenesis, the absence of specific therapeutic options remains a challenge in the prevention and treatment of flaviviral infections. Through the intricate processes of fusion, transcription, replication, and maturation, the complex interplay of viral and host metabolic interactions affects pathophysiology. Crucial interactions involve metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, each playing a pivotal role in the replication and maturation of flaviviruses. These viral-host metabolic molecular interactions hijack and modulate the molecular mechanisms of host metabolism. A comprehensive understanding of these intricate metabolic pathways offers valuable insights, potentially unveiling novel targets for therapeutic interventions against flaviviral pathogenesis. This review emphasizes promising avenues for the development of therapeutic agents that target specific metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, which interact with flavivirus replication and are closely linked to the modulation of host metabolism. The clinical limitations of current drugs have prompted the development of new inhibitory strategies for flaviviruses based on an understanding of the molecular interactions between the virus and the host.

Keywords:  Flavivirus; Inhibitors; Metabolism; Nonstructural proteins; Vaccines; Virus-host interaction

DOI:  https://doi.org/10.5501/wjv.v13.i4.99110
Sci Rep. 2024 Dec 28. 14(1): 30679

Nitazoxanide controls virus viability through its impact on membrane bioenergetics.

Noureddine Hammad, Céline Ransy, Benoit Pinson, Jeremy Talmasson, Christian Bréchot, Jean-François Rossignol, Frédéric Bouillaud.

  Viruses are dependent on cellular energy metabolism for their replication, and the drug nitazoxanide (Alinia) was shown to interfere with both processes. Nitazoxanide is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that mitochondrial uncoupling underlies the antiviral effects of nitazoxanide. Tizoxanide (the active metabolite of nitazoxanide), its derivative RM4848 and the uncoupler CCCP were applied to a virus-releasing cell line to obtain the same increasing levels of mitochondrial uncoupling, hence identical impact on OXPHOS. A decrease in infectious viral particle release was observed and reflected the intensity of impact on OXPHOS, irrespective of the nature of the drug. The antiviral effect was significant although the impact on OXPHOS was modest (≤ 25%), and disappeared when a high concentration (25 mM) of glucose was used to enhance glycolytic generation of ATP. Accordingly, the most likely explanation is that moderate interference with mitochondrial OXPHOS induced rearrangement of ATP use and acquisition of infective properties of the viral particles be highly sensitive to this rearrangement. The antiviral effect of nitazoxanide has been supported by clinical trials, and nitazoxanide is considered a safe drug. However, serious adverse effects of the uncoupler dinitrophenol occurred when used to increase significantly metabolic rate with the purpose of weight loss. Taken together, while impairment of mitochondrial bioenergetics is an unwanted drug effect, moderate interference should be considered as a basis for therapeutic efficacy.

Keywords:  ATP use; Antiviral; Cellular bioenergetics; Glucose metabolism; Mitochondria; Mitochondrial uncoupling

DOI:  https://doi.org/10.1038/s41598-024-78694-8
Metabolites. 2024 Nov 25. pii: 656. [Epub ahead of print]14(12):

Longitudinal Metabolomics Reveals Metabolic Dysregulation Dynamics in Patients with Severe COVID-19.

Ryo Uchimido, Kenjiro Kami, Hiroyuki Yamamoto, Ryo Yokoe, Issei Tsuchiya, Yoko Nukui, Yuki Goto, Mariko Hanafusa, Takeo Fujiwara, Kenji Wakabayashi.

  Background/Objective: A dysregulated metabolism has been studied as a key aspect of the COVID-19 pathophysiology, but its longitudinal progression in severe cases remains unclear. In this study, we aimed to investigate metabolic dysregulation over time in patients with severe COVID-19 requiring mechanical ventilation (MV). Methods: In this single-center, prospective, observational study, we obtained 236 serum samples from 118 adult patients on MV in an ICU. The metabolite measurements were performed using capillary electrophoresis Fourier transform mass spectrometry, and we categorized the sampling time points into three time zones to align them with the disease progression: time zone 1 (T1) (the hyperacute phase, days 1-3 post-MV initiation), T2 (the acute phase, days 4-14), and T3 (the chronic phase, days 15-30). Using volcano plots and enrichment pathway analyses, we identified the differential metabolites (DMs) and enriched pathways (EPs) between the survivors and non-survivors for each time zone. The DMs and EPs were further grouped into early-stage, late-stage, and consistent groups based on the time zones in which they were detected. Results: With the 566 annotated metabolites, we identified 38 DMs and 17 EPs as the early-stage group, which indicated enhanced energy production in glucose, amino acid, and fatty acid metabolisms in non-survivors. As the late-stage group, 84 DMs and 10 EPs showed upregulated sphingolipid, taurine, and tryptophan-kynurenine metabolisms with downregulated steroid hormone synthesis in non-survivors. Three DMs and 23 EPs in the consistent group showed more pronounced dysregulation in the dopamine and arachidonic acid metabolisms across all three time zones in non-survivors. Conclusions: This study elucidated the temporal differences in metabolic dysregulation between survivors and non-survivors of severe COVID-19, offering insights into its longitudinal progression and disease mechanisms.

Keywords:  longitudinal metabolic dysregulation; severe COVID-19

DOI:  https://doi.org/10.3390/metabo14120656
PLoS Pathog. 2024 Dec 26. 20(12): e1012815

Human cytomegalovirus RNA2.7 inhibits ferroptosis by upregulating ferritin and GSH via promoting ZNF395 degradation.

Mingyi Xu, Shan Ruan, Jingxuan Sun, Jianming Li, Dan Chen, Yanping Ma, Ying Qi, Zhongyang Liu, Qiang Ruan, Yujing Huang.

Human cytomegalovirus (HCMV) is a herpes virus with a long replication cycle. HCMV encoded long non-coding RNA termed RNA2.7 is the dominant transcript with a length of about 2.5kb, accounting for 25% of total viral transcripts. Studies have shown that HCMV RNA2.7 inhibits apoptosis caused by infection. The effect of RNA2.7 on other forms of cell death is still unclear. In this work, we found that RNA2.7 deletion significantly decreased the viability of HCMV-infected cells, while treatment with ferroptosis inhibitor Fer-1 rescued the infection-induced cell death, demonstrating an anti-ferroptosis role of RNA2.7. The results further showed that RNA2.7 inhibited ferroptosis via enhancing Ferritin Heavy Chain 1 (FTH1) and Solute Carrier Family 7 Member 11 (SLC7A11) expression in Erastin treated cells without involving other viral components. Pooled Genome-wide CRISPR screening revealed zinc finger protein 395 (ZNF395) as a new regulator repressing the expression of FTH1 and SLC7A11. HCMV RNA2.7 promoted proteasome-mediated degradation of ZNF395 that resulted in upregulation of FTH1 and SLC7A11 to inhibit ferroptosis, therefore maintain survival in host cells and complete replication of virus.

DOI: https://doi.org/10.1371/journal.ppat.1012815