bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2023–12–31
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. ESCRT machinery and virus infection.
  2. Cholesterol depletion inhibits rabies virus infection by restricting viral adsorption and fusion.
  3. Cell-type dependence of necroptosis pathways triggered by viral infection.
  4. Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.
  5. Pseudorabies virus causes splenic injury via inducing oxidative stress and apoptosis related factors in mice.
  6. The interplay of TGF-β1 and cholesterol orchestrating hepatocyte cell fate, EMT, and signals for HSC activation.
  7. Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study.
  1. Antiviral Res. 2023 Dec 24. pii: S0166-3542(23)00264-4. [Epub ahead of print] 105786
    ESCRT machinery and virus infection.
    Jun Dai, Yiyi Feng, Ying Liao, Lei Tan, Yingjie Sun, Cuiping Song, Xusheng Qiu, Chan Ding.
      The endosomal sorting complex required for transport (ESCRT) machinery plays a significant role in the spread of human viruses. However, our understanding of how the host ESCRT machinery responds to viral infection remains limited. Emerging evidence suggests that the ESCRT machinery can be hijacked by viruses of different families to enhance their replication. Throughout their life cycle, these viruses can interfere with or exploit ESCRT-mediated physiological processes to increase their chances of infecting the host. In contrast, to counteract virus infection, the interferon-stimulated gene 15 (ISG15) or the E3 ISG15-protein ligase (HERC5) system within the infected cells is activated to degrade the ESCRT proteins. Many retroviral and RNA viral proteins have evolved "late (L) domain" motifs, which enable them to recruit host ESCRT subunit proteins to facilitate virus transport, replication, budding, mature, and even endocytosis, Therefore, the L domain motifs and ESCRT subunit proteins could serve as promising drug targets for antiviral therapy. This review investigated the composition and essential functions of the ESCRT, shedding light on the impact of ESCRT subunits and viral L domain motifs on the replication of viruses. Furthermore, the antiviral effects facilitated by the ESCRT machinery have been investigated, aiming to provide valuable insights to guide the development and utilization of antiviral drugs.
    Keywords:  Antiviral; Drugs; ESCRT; Hijacking; Machinery; Virus
    DOI:  https://doi.org/10.1016/j.antiviral.2023.105786
  2. Vet Microbiol. 2023 Dec 14. pii: S0378-1135(23)00306-1. [Epub ahead of print]289 109952
    Cholesterol depletion inhibits rabies virus infection by restricting viral adsorption and fusion.
    Qingxiu Hou, Caiqian Wang, Jingyi Xiong, Haoran Wang, Zhihui Wang, Juanjuan Zhao, Qiong Wu, Zhen F Fu, Ling Zhao, Ming Zhou.
      Rabies is an ancient zoonotic disease caused by the rabies virus (RABV), and a sharp increase in rabies cases and deaths were observed following the COVID-19 pandemic, indicating that it still poses a severe public health threat in most countries in the world. Cholesterol is one of the major lipid components in cells, and the exact role of cholesterol in RABV infection remains unclear. In this study, we initially observed that cellular cholesterol levels were significantly elevated in RABV infected cells, while cholesterol depletion by using methyl-β-cyclodextrin (MβCD) could restrict RABV entry. We further found that decreasing the cholesterol level of the viral envelope could change the bullet-shaped morphology of RABV and dislodge the glycoproteins on its surface to affect RABV entry. Moreover, the depletion of cholesterol could decrease lysosomal cholesterol accumulation to inhibit RABV fusion. Finally, it was found that the depletion of cholesterol by MβCD was due to the increase of oxygen sterol production in RABV-infected cells and the enhancement of cholesterol efflux by activating liver X receptor alpha (LXRα). Together, our study reveals a novel role of cholesterol in RABV infection, providing new insight into explore of effective therapeutics for rabies.
    Keywords:  Cholesterol; Cholesterol efflux; Morphological change; MβCD; Rabies virus
    DOI:  https://doi.org/10.1016/j.vetmic.2023.109952
  3. FEBS J. 2023 Dec 25.
    Cell-type dependence of necroptosis pathways triggered by viral infection.
    Heather Koehler, Derek Titus, Crystal Lawson.
      Necroptosis, a potent host defense mechanism, limits viral replication and pathogenesis through three distinct initiation pathways. Toll-like receptor (TLR) 3 via TRIF, Z-DNA-binding protein 1 (ZBP1), and tumor necrosis factor α (TNF) mediate necroptosis, with ZBP1 and TNF playing pivotal roles in controlling viral infections with the role of TLR3-TRIF being less clear. ZBP1-mediated necroptosis is initiated when host ZBP1 senses viral Z-RNA and recruits receptor-interacting serine/threonine-protein kinase 3 (RIPK3), driving a MLKL-dependent necroptosis pathway, whereas TNF-mediated necroptosis is initiated by TNF signaling, which drives a RIPK1-RIPK3-MLKL pathway, resulting in necroptosis. Certain viruses (cytomegalovirus, herpes simplex virus, and vaccinia) have evolved to produce proteins that compete with host defense systems, preventing programmed cell death pathways from being initiated. Two engineered viruses deficient of active forms of these proteins, murine cytomegalovirus M45mutRHIM and vaccinia virus E3∆Zα, trigger ZBP1-dependent necroptosis in mouse embryonic fibroblasts (MEFs). In contrast, when bone-marrow-derived macrophages (BMDMs) are infected with the viruses, necroptosis is initiated predominantly through the TNF-mediated pathway. However, when the TNF pathway is blocked by RIPK1 inhibitors or a TNF blockade, ZBP1-mediated necroptosis becomes the prominent pathway in BMDMs. Overall, these data implicate a cell-type preference for either TNF-mediated or ZBP1-mediated necroptosis pathways in host responses to viral infections. These preferences are important to consider when evaluating disease models that incorporate necroptosis, as they may contribute to tissue-specific reactions that could alter the balance of inflammation versus control of virus, impacting the organism as a whole.
    Keywords:  BMDM; Cell death; MEF; RIPK1; TNF; Virus; ZBP1
    DOI:  https://doi.org/10.1111/febs.17045
  4. Genes Immun. 2023 Dec 25.
    Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.
    José J Fernández, Cristina Mancebo, Sonsoles Garcinuño, Gabriel March, Yolanda Alvarez, Sara Alonso, Luis Inglada, Jesús Blanco, Antonio Orduña, Olimpio Montero, Tito A Sandoval, Juan R Cubillos-Ruiz, Elena Bustamante-Munguira, Nieves Fernández, Mariano Sánchez Crespo.
      The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.
    DOI:  https://doi.org/10.1038/s41435-023-00243-6
  5. Sci Rep. 2023 Dec 27. 13(1): 23011
    Pseudorabies virus causes splenic injury via inducing oxidative stress and apoptosis related factors in mice.
    Wei Sun, Shanshan Liu, Yi Yan, Qingyan Wang, Yu Fan, Samuel Kumi Okyere.
      Pseudorabies virus (PRV) is an immunosuppressive virus that causes significant damage to the pig industry. This study aimed to investigate the effects of PRV on oxidative stress and apoptotic related in the spleen of mice to provide basis knowledge for further research on the pathogenesis of PRV in mice model. 36 mice were randomly two groups, the control group which only received 200 μL PBS and infection group which was subcutaneously infected with 200 μL of 1 × 103 TCID50/100 μL PRV, respectively. Spleen tissues in each group were collected for further experiments at 48, 72, and 96 h post-infection (hpi). Pathological observation was performed by hematoxylin and eosin Y staining. Biochemical and Flow cytometry methods were used to determine the reactive oxygen species profile and apoptosis of the spleen post-infection and apoptosis detection. In addition, q-PCR and Western blot were adopted to measure the apoptotic conditions of the spleen infected with PRV. The results indicated that the reactive oxygen species (ROS) level in the PRV infection group was remarkedly increased (p < 0.01) at a time-dependent pattern. Furthermore, the Malondialdehyde levels in the spleen of mice in the infection group increased (p < 0.01) in a time-dependent mode. However, the activity of Catalase, Superoxide dismutase, and glutathione peroxidase and the content of Glutathione in the infection group were decreased with the control group (p < 0.01) at a time-dependent manner. In addition, the ratio of splenocyte apoptosis in the infection group significantly increased (p < 0.01) in a time-dependent manner. In conclusion, PRV infection causes apoptosis of the spleen via oxidative stress in mice.
    DOI:  https://doi.org/10.1038/s41598-023-50431-7
  6. Cell Mol Gastroenterol Hepatol. 2023 Dec 26. pii: S2352-345X(23)00228-X. [Epub ahead of print]
    The interplay of TGF-β1 and cholesterol orchestrating hepatocyte cell fate, EMT, and signals for HSC activation.
    Sai Wang, Frederik Link, Mei Han, Roohi Chaudhary, Anastasia Asimakopoulos, Roman Liebe, Ye Yao, Seddik Hammad, Anne Dropmann, Marinela Krizanac, Claudia Rubie, Laura Kim Feiner, Matthias Glanemann, Matthias P A Ebert, Ralf Weiskirchen, Yoav I Henis, Marcelo Ehrlich, Steven Dooley.
       BACKGROUND AND AIMS: Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the reciprocal regulation of TGF-β1 signaling and cholesterol metabolism in MASLD is yet unknown.
    METHODS: Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA-Seq of murine hepatocyte cell line (AML12) and mouse primary hepatocytes (MPH) treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment (CE) or depletion (CD)), and on mice injected with adeno-associated virus 8 (AAV8)-Control/TGF-β1.
    RESULTS: TGF-β1 inhibited mRNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, MPHs, and AAV8-TGF-β1-treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue were also reduced upon TGF-β1 treatment. Smad2/3 phosphorylation following 2 h TGF-β1 treatment persisted after CE or CD and was mildly increased following CD, while TGF-β1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 h incubation with TGF-β1, including EMT, actin polymerization, and apoptosis. CD mimicked the outcome of long term TGF-β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. Additionally, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells.
    CONCLUSIONS: TGF-β1 inhibits cholesterol metabolism while cholesterol attenuates TGF-β1 downstream effects in hepatocytes.
    Keywords:  Cholesterol metabolism; MASLD; TGF-β1; hepatic fibrosis
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.12.012
  7. Int J Tryptophan Res. 2023 ;16 11786469231220781
    Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study.
    Maja Taenzer, Judith Löffler-Ragg, Andrea Schroll, Pablo Monfort-Lanzas, Sabine Engl, Günter Weiss, Natascha Brigo, Katharina Kurz.
       Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis.
    Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis.
    Patients and Methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined.
    Results and Conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety. Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations.
    Keywords:  IFN-gamma mediated pathway; Long-COVID; fatigue; gut dysbiosis; urine metabolites
    DOI:  https://doi.org/10.1177/11786469231220781
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