bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024‒02‒25
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Newcastle disease virus regulates its replication by instigating oxidative stress-driven Sirtuin 7 production.
  2. Cholesterol: A friend to viruses.
  3. Impact of Delta SARS-CoV-2 Infection on Glucose Metabolism: Insights on Host Metabolism and Virus Crosstalk in a Feline Model.
  4. Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells.
  5. TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions.
  6. Plasma Metabonomics of Human Adenovirus-infected Patients with Pneumonia and Upper Respiratory Tract Infection.
  7. IL-15 reprogramming compensates for NK cell mitochondrial dysfunction in HIV-1 infection.
  8. Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry.
  9. Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.
  10. SIV Infection Is Associated with Transient Acute-Phase Steatosis in Hepatocytes In Vivo.
  1. J Gen Virol. 2024 Feb;105(2):
    Newcastle disease virus regulates its replication by instigating oxidative stress-driven Sirtuin 7 production.
    Kamal Shokeen, Sachin Kumar.
      Reactive oxygen species (ROS) accumulation inside the cells instigates oxidative stress, activating stress-responsive genes. The viral strategies for promoting stressful conditions and utilizing the induced host proteins to enhance their replication remain elusive. The present work investigates the impact of oxidative stress responses on Newcastle disease virus (NDV) pathogenesis. Here, we show that the progression of NDV infection varies with intracellular ROS levels. Additionally, the results demonstrate that NDV infection modulates the expression of oxidative stress-responsive genes, majorly sirtuin 7 (SIRT7), a NAD+-dependent deacetylase. The modulation of SIRT7 protein, both through overexpression and knockdown, significantly impacts the replication dynamics of NDV in DF-1 cells. The activation of SIRT7 is found to be associated with the positive regulation of cellular protein deacetylation. Lastly, the results suggested that NDV-driven SIRT7 alters NAD+ metabolism in vitro and in ovo. We concluded that the elevated expression of NDV-mediated SIRT7 protein with enhanced activity metabolizes the NAD+ to deacetylase the host proteins, thus contributing to high virus replication.
    Keywords:  Deacetylation; Newcastle disease virus; nicotinamide adenine dinucleotide ; oxidative stress; reactive oxygen species; sirtuin
    DOI:  https://doi.org/10.1099/jgv.0.001961
  2. Int Rev Immunol. 2024 Feb 19. 1-15
    Cholesterol: A friend to viruses.
    Yingchun Wang, Lifen Gao.
      Cholesterol is a key life-sustaining molecule which regulates membrane fluidity and serves as a signaling mediator. Cholesterol homeostasis is closely related to various pathological conditions including tumor, obesity, atherosclerosis, Alzheimer's disease and viral infection. Viral infection disrupts host cholesterol homeostasis, facilitating their own survival. Meanwhile, the host cells strive to reduce cholesterol accessibility to limit viral infection. This review focuses on the regulation of cholesterol metabolism and the role of cholesterol in viral infection, specifically providing an overview of cholesterol as a friend to promote viral entry, replication, assembly, release and immune evasion, which might inspire valuable thinking for pathogenesis and intervention of viral infection.
    Keywords:  Antiviral therapy; cholesterol metabolism; host defense; viral infection
    DOI:  https://doi.org/10.1080/08830185.2024.2314577
  3. Viruses. 2024 Feb 15. pii: 295. [Epub ahead of print]16(2):
    Impact of Delta SARS-CoV-2 Infection on Glucose Metabolism: Insights on Host Metabolism and Virus Crosstalk in a Feline Model.
    Matthew T Rochowski, Kaushalya Jayathilake, John-Michael Balcerak, Miruthula Tamil Selvan, Sachithra Gunasekara, Craig Miller, Jennifer M Rudd, Véronique A Lacombe.
      Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes enhanced mortality in people with metabolic and cardiovascular diseases. Other highly infectious RNA viruses have demonstrated dependence on glucose transport and utilization, so we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole-body glucose metabolism. Twenty-four healthy domestic cats were intratracheally inoculated with B.1.617.2 (delta) SARS-CoV-2 and samples were collected at 4- and 12-days post-inoculation (dpi). Blood glucose and circulating cortisol concentrations were elevated at 4 and 12 dpi. Serum insulin concentration was statistically significantly decreased, while angiotensin 2 concentration was elevated at 12 dpi. SARS-CoV-2 RNA was detected in the pancreas and skeletal muscle at low levels; however, no change in the number of insulin-producing cells or proinflammatory cytokines was observed in the pancreas of infected cats through 12 dpi. SARS-CoV-2 infection statistically significantly increased GLUT protein expression in both the heart and lungs, correlating with increased AMPK expression. In brief, SARS-CoV-2 increased blood glucose concentration and cardio-pulmonary GLUT expression through an AMPK-dependent mechanism, without affecting the pancreas, suggesting that SARS-CoV-2 induces the reprogramming of host glucose metabolism. A better understanding of host cell metabolism and virus crosstalk could lead to the discovery of novel metabolic therapeutic targets for patients affected by COVID-19.
    Keywords:  AMPK; COVID-19; GLUT; angiotensin 2; cortisol; insulin
    DOI:  https://doi.org/10.3390/v16020295
  4. Viruses. 2024 Jan 31. pii: 212. [Epub ahead of print]16(2):
    Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells.
    Stacia M Dolliver, Caleb Galbraith, Denys A Khaperskyy.
      Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is the inhibition of the integrated stress response-the mechanism through which infected cells arrest translation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α). We have recently shown that the human common cold betacoronavirus OC43 actively inhibits eIF2α phosphorylation in response to sodium arsenite, a potent inducer of oxidative stress. In this work, we examined the modulation of integrated stress responses by OC43 and demonstrated that the negative feedback regulator of eIF2α phosphorylation GADD34 is strongly induced in infected cells. However, the upregulation of GADD34 expression induced by OC43 was independent from the activation of the integrated stress response and was not required for the inhibition of eIF2α phosphorylation in virus-infected cells. Our work reveals a complex interplay between the common cold coronavirus and the integrated stress response, in which efficient viral protein synthesis is ensured by the inhibition of eIF2α phosphorylation but the GADD34 negative feedback loop is disrupted.
    Keywords:  ATF4; GADD34; PERK; PKR; betacoronavirus OC43; integrated stress response
    DOI:  https://doi.org/10.3390/v16020212
  5. Cell Commun Signal. 2024 Feb 21. 22(1): 142
    TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions.
    Laxman Manandhar, Raghbendra Kumar Dutta, Pradeep Devkota, Arun Chhetri, Xiaofan Wei, Channy Park, Hyug Moo Kwon, Raekil Park.
      BACKGROUND: Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown.METHODS: To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion.
    RESULTS: This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation.
    CONCLUSIONS: Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing.
    Keywords:  Autophagy; Calcium; Catalase; Peroxisome; ROS; TFEB
    DOI:  https://doi.org/10.1186/s12964-024-01524-x
  6. Curr Med Sci. 2024 Feb;44(1): 121-133
    Plasma Metabonomics of Human Adenovirus-infected Patients with Pneumonia and Upper Respiratory Tract Infection.
    Ting-Ting Wei, Wen Xu, Bo Tu, Wan-Xue Zhang, Xin-Xin Yang, Yiguo Zhou, Shan-Shan Zhang, Jun-Lian Yang, Ming-Zhu Xie, Juan Du, Wei-Wei Chen, Qing-Bin Lu.
      OBJECTIVE: Human adenovirus (HAdV) infection is common and can develop to serious conditions with high mortality, yet the mechanism of HAdV infection remains unclear. In the present study, the serum metabolite profiles of HAdV-7-infected patients with pneumonia or upper respiratory tract infection (URTI) were explored.METHODS: In total, 35 patients were enrolled in the study following an outbreak of HAdV-7 in the army, of whom 14 had pneumonia and 21 had URTI. Blood samples were collected at the acute stage and at the recovery stage and were analyzed by untargeted metabolomics.
    RESULTS: Over 90% of the differential metabolites identified between the pneumonia patients and URTI patients were lipids and lipid-like molecules, including glycerophospholipids, fatty acyls, and sphingolipids. The metabolic pathways that were significantly enriched were primarily the lipid metabolism pathways, including sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. The sphingolipid metabolism was identified as a significantly differential pathway between the pneumonia patients and URTI patients and between the acute and recovery stages for the pneumonia patients, but not between the acute and recovery stages for the URTI patients. Ceramide and lactosylceramide, involved in sphingolipid metabolism, were significantly higher in the pneumonia patients than in the URTI patients with good discrimination abilities [area under curve (AUC) 0.742 and 0.716, respectively; combination AUC 0.801].
    CONCLUSION: Our results suggested that HAdV modulated lipid metabolism for both the patients with URTI and pneumonia, especially the sphingolipid metabolism involving ceramide and lactosylceramide, which might thus be a potential intervention target in the treatment of HAdV infection.
    Keywords:  human adenovirus; lipids; metabonomic; pneumonia; upper respiratory tract infection
    DOI:  https://doi.org/10.1007/s11596-024-2835-9
  7. JCI Insight. 2024 Jan 16. pii: e173099. [Epub ahead of print]9(4):
    IL-15 reprogramming compensates for NK cell mitochondrial dysfunction in HIV-1 infection.
    Elia Moreno-Cubero, Aljawharah Alrubayyi, Stefan Balint, Ane Ogbe, Upkar S Gill, Rebecca Matthews, Sabine Kinloch, Fiona Burns, Sarah L Rowland-Jones, Persephone Borrow, Anna Schurich, Michael Dustin, Dimitra Peppa.
      Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation, including NK cell responses. Persistent HIV-1 infection leads to a state of chronic immune activation, NK cell subset redistribution, and progressive NK cell dysregulation. In this study, we examined the metabolic processes that characterize NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in HIV-1- individuals infected with human cytomegalovirus (HCMV). However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS). Defective OXPHOS was accompanied by increased mitochondrial depolarization, structural alterations, and increased DRP-1 levels promoting fission, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for the NK cell response to receptor stimulation was alleviated upon IL-15 pretreatment, which enhanced mammalian target of rapamycin complex 1 (mTORC1) activity. IL-15 priming enhanced NK cell functionality to anti-CD16 stimulation in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.
    Keywords:  AIDS/HIV; Immunology; Mitochondria; NK cells
    DOI:  https://doi.org/10.1172/jci.insight.173099
  8. Life Sci Alliance. 2024 May;pii: e202302453. [Epub ahead of print]7(5):
    Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry.
    Thomas Grewal, Mai Khanh Linh Nguyen, Christa Buechler.
      The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities to lower SARS-CoV-2 infection rates and improve COVID-19 outcome. This includes cellular cholesterol, which is critical for viral spike proteins to capture the host machinery for SARS-CoV-2 cell entry. Once endocytosed, exit of SARS-CoV-2 from the late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release of new viral particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, and ezetimibe have revealed potential to protect against COVID-19. In addition, pharmacological inhibition of cholesterol exiting late endosomes/lysosomes identified drug candidates, including antifungals, to block SARS-CoV-2 infection. This review describes the multiple roles of cholesterol at the cell surface and endolysosomes for SARS-CoV-2 entry and the potential of drugs targeting cholesterol homeostasis to reduce SARS-CoV-2 infectivity and COVID-19 disease severity.
    DOI:  https://doi.org/10.26508/lsa.202302453
  9. J Med Virol. 2024 Feb;96(2): e29472
    Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.
    Dong Yang, Jasper Fuk-Woo Chan, Chaemin Yoon, Tsz-Yat Luk, Huiping Shuai, Yuxin Hou, Xiner Huang, Bingjie Hu, Yue Chai, Terrence Tsz-Tai Yuen, Yuanchen Liu, Tianrenzheng Zhu, Huan Liu, Jialu Shi, Yang Wang, Yixin He, Ko-Yung Sit, Wing-Kuk Au, Anna Jinxia Zhang, Shuofeng Yuan, Bao-Zhong Zhang, Yao-Wei Huang, Hin Chu.
      Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNβ treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.
    Keywords:  COVID-19; IDO1; SARS-CoV-2; ex vivo human lung tissues; indoleamine 2,3-dioxygenase; interferon; type-II IFN
    DOI:  https://doi.org/10.1002/jmv.29472
  10. Viruses. 2024 Feb 15. pii: 296. [Epub ahead of print]16(2):
    SIV Infection Is Associated with Transient Acute-Phase Steatosis in Hepatocytes In Vivo.
    Nina Derby, Sreya Biswas, Sofiya Yusova, Cristina Luevano-Santos, Maria Cristina Pacheco, Kimberly A Meyer, Brooke I Johnson, Miranda Fischer, Katherine A Fancher, Cole Fisher, Yohannes M Abraham, Conor J McMahon, Savannah S Lutz, Jeremy V Smedley, Benjamin J Burwitz, Donald L Sodora.
      Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a major cause of morbidity and mortality in HIV-infected individuals, even those receiving optimal antiretroviral therapy. Here, we utilized the SIV rhesus macaque model and advanced laparoscopic techniques for longitudinal collection of liver tissue to elucidate the timing of pathologic changes. The livers of both SIV-infected (N = 9) and SIV-naïve uninfected (N = 8) macaques were biopsied and evaluated at four time points (weeks -4, 2, 6, and 16-20 post-infection) and at necropsy (week 32). SIV DNA within the macaques' livers varied by over 4 logs at necropsy, and liver SIV DNA significantly correlated with SIV RNA in the plasma throughout the study. Acute phase liver pathology (2 weeks post-infection) was characterized by evidence for fat accumulation (microvesicular steatosis), a transient elevation in both AST and cholesterol levels within the serum, and increased hepatic expression of the PPARA gene associated with cholesterol metabolism and beta oxidation. By contrast, the chronic phase of the SIV infection (32 weeks post-infection) was associated with sinusoidal dilatation, while steatosis resolved and concentrations of AST and cholesterol remained similar to those in uninfected macaques. These findings suggest differential liver pathologies associated with the acute and chronic phases of infection and the possibility that therapeutic interventions targeting metabolic function may benefit liver health in people newly diagnosed with HIV.
    Keywords:  HIV; SIV; biopsy; hepatocyte; histology; liver; metabolism; steatosis
    DOI:  https://doi.org/10.3390/v16020296
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