bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024‒02‒04
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Virus-induced host cell metabolic alteration.
  2. Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
  3. Metabolomic landscape of macrophage discloses an anabolic signature of dengue virus infection and antibody-dependent enhancement of viral infection.
  4. Human cytomegalovirus modulates mTORC1 to redirect mRNA translation within quiescently infected monocytes.
  5. Impaired influenza A virus replication by the host restriction factor SAMHD1 which inhibited by PA-mediated dephosphorylation of the host transcription factor IRF3.
  6. Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.
  7. Effect of HPV Oncoprotein on Carbohydrate and Lipid Metabolism in Tumor Cells.
  1. Rev Med Virol. 2024 Jan;34(1): e2505
    Virus-induced host cell metabolic alteration.
    Syed Shahariar Bappy, Md Muzammal Haque Asim, Mohammad Mainul Ahasan, Asif Ahsan, Sorna Sultana, Roksana Khanam, Abu Zaffar Shibly, Yearul Kabir.
      Viruses change the host cell metabolism to produce infectious particles and create optimal conditions for replication and reproduction. Numerous host cell pathways have been modified to ensure available biomolecules and sufficient energy. Metabolomics studies conducted over the past decade have revealed that eukaryotic viruses alter the metabolism of their host cells on a large scale. Modifying pathways like glycolysis, fatty acid synthesis and glutaminolysis could provide potential energy for virus multiplication. Thus, almost every virus has a unique metabolic signature and a different relationship between the viral life cycle and the individual metabolic processes. There are enormous research in virus induced metabolic reprogramming of host cells that is being conducted through numerous approaches using different vaccine candidates and antiviral drug substances. This review provides an overview of viral interference to different metabolic pathways and improved monitoring in this area will open up new ways for more effective antiviral therapies and combating virus induced oncogenesis.
    Keywords:  glutaminolysis; glycolysis; metabolism; virus
    DOI:  https://doi.org/10.1002/rmv.2505
  2. FASEB J. 2024 Feb 15. 38(3): e23450
    Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
    Chengcheng Peng, Pengpeng Xiao, Nan Li.
      Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.
    Keywords:  glucose metabolism; glutamine metabolism; immune microenvironment; lipid metabolism; metabolic reprogramming; oncolytic virus; oxidative phosphorylation
    DOI:  https://doi.org/10.1096/fj.202301947RR
  3. PLoS Negl Trop Dis. 2024 Feb 02. 18(2): e0011923
    Metabolomic landscape of macrophage discloses an anabolic signature of dengue virus infection and antibody-dependent enhancement of viral infection.
    Li Xu, Min Li, Jingpu Zhang, Dongxiao Li, Jie Tao, Fuchun Zhang, Xia Jin, Jiahai Lu, Tiefu Liu.
      Dengue virus (DENV) infection causes dengue fever, the most prevalent arthropod-transmitted viral disease worldwide. Viruses are acellular parasites and obligately rely on host cell machinery for reproduction. Previous studies have indicated metabolomic changes in endothelial cell models and sera of animal models and patients with dengue fever. To probe the immunometabolic mechanism of DENV infection, here, we report the metabolomic landscape of a human macrophage cell model of DENV infection and its antibody-dependent enhancement. DENV infection of THP-1-derived macrophages caused 202 metabolic variants, of which amino acids occupied 23.7%, fatty acids 21.78%, carbohydrates 10.4%, organic acids 13.37%, and carnitines 10.4%. These metabolomic changes indicated an overall anabolic signature, which was characterized by the global exhaustion of amino acids, increases of cellular fatty acids, carbohydrates and pentoses, but decreases of acylcarnitine. Significant activation of metabolic pathways of glycolysis, pentose phosphate, amino acid metabolism, and tricarboxylic acid cycle collectively support the overall anabolism to meet metabolic demands of DENV replication and immune activation by viral infection. Totally 88 of 202 metabolic variants were significantly changed by DENV infection, 36 of which met the statistical standard (P<0.05, VIP>1.5) of differentially expressed metabolites, which were the predominantly decreased variants of acylcarnitine and the increased variants of fatty acids and carbohydrates. Remarkably, 11 differentially expressed metabolites were significantly distinct between DENV only infection and antibody-dependent enhancement of viral infection. Our data suggested that the anabolic activation by DENV infection integrates the viral replication and anti-viral immune activation.
    DOI:  https://doi.org/10.1371/journal.pntd.0011923
  4. J Virol. 2024 Jan 30. e0188823
    Human cytomegalovirus modulates mTORC1 to redirect mRNA translation within quiescently infected monocytes.
    Michael J Miller, Dilruba Akter, Jamil Mahmud, Gary C Chan.
      Human cytomegalovirus (HCMV) utilizes peripheral blood monocytes as a means to systemically disseminate throughout the host. Following viral entry, HCMV stimulates non-canonical Akt signaling leading to the activation of mTORC1 and the subsequent translation of select antiapoptotic proteins within infected monocytes. However, the full extent to which the HCMV-initiated Akt/mTORC1 signaling axis reshapes the monocyte translatome is unclear. We found HCMV entry alone was able to stimulate widescale changes to mRNA translation levels and that inhibition of mTOR, a component of mTORC1, dramatically attenuated HCMV-induced protein synthesis. Although monocytes treated with normal myeloid growth factors also exhibited increased levels of translation, mTOR inhibition had no effect, suggesting HCMV activation of mTOR stimulates the acquisition of a unique translatome within infected monocytes. Indeed, polyribosomal profiling of HCMV-infected monocytes identified distinct prosurvival transcripts that were preferentially loaded with ribosomes when compared to growth factor-treated cells. Sirtuin 1 (SIRT1), a deacetylase that exerts prosurvival effects through regulation of the PI3K/Akt pathway, was found to be highly enriched following HCMV infection in an mTOR-dependent manner. Importantly, SIRT1 inhibition led to the death of HCMV-infected monocytes while having minimal effect on uninfected cells. SIRT1 also supported a positive feedback loop to sustain Akt/mTORC1 signaling following viral entry. Taken together, HCMV profoundly reshapes mRNA translation in an mTOR-dependent manner to enhance the synthesis of select factors necessary for the survival of infected monocytes.IMPORTANCEHuman cytomegalovirus (HCMV) infection is a significant cause of morbidity and mortality among the immunonaïve and immunocompromised. Peripheral blood monocytes are a major cell type responsible for disseminating the virus from the initial site of infection. In order for monocytes to mediate viral spread within the host, HCMV must subvert the naturally short lifespan of these cells. In this study, we performed polysomal profiling analysis, which demonstrated HCMV to globally redirect mRNA translation toward the synthesis of cellular prosurvival factors within infected monocytes. Specifically, HCMV entry into monocytes induced the translation of cellular SIRT1 to generate an antiapoptotic state. Defining the precise mechanisms through which HCMV stimulates survival will provide insight into novel anti-HCMV drugs able to target infected monocytes.
    Keywords:  cytomegalovirus; monocytes; translation
    DOI:  https://doi.org/10.1128/jvi.01888-23
  5. Virol J. 2024 Jan 29. 21(1): 33
    Impaired influenza A virus replication by the host restriction factor SAMHD1 which inhibited by PA-mediated dephosphorylation of the host transcription factor IRF3.
    Zhilei Zhao, Shuyi Han, Qingxun Zhang, Ye Wang, Kening Yue, Salbia Abbas, Hongxuan He.
      BACKGROUND: Influenza A virus (IAV) can cause severe and life-threatening illness in humans and animals. Therefore, it is important to search for host antiviral proteins and elucidate their antiviral mechanisms for the development of potential treatments. As a part of human innate immunity, host restriction factors can inhibit the replication of viruses, among which SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) can restrict the replication of viruses, such as HIV and enterovirus EV71. Viruses also developed countermeasures in the arms race with their hosts. There are few reports about whether SAMHD1 has a restriction effect on IAV.METHODS: To investigate the impact of IAV infection on SAMHD1 expression in A549 cells, we infected A549 cells with a varying multiplicity of infection (MOI) of IAV and collected cell samples at different time points for WB and RT-qPCR analysis to detect viral protein and SAMHD1 levels. The virus replication level in the cell culture supernatant was determined using TCID50 assay. Luciferase assay was used to reveal that H5N1 virus polymerase acidic protein (PA) affected the activity of the SAMHD1 promoter. To assess the antiviral capacity of SAMHD1, we generated a knockdown and overexpressed cell line for detecting H5N1 replication.
    RESULTS: In this study, we observed that SAMHD1 can restrict the intracellular replication of H5N1 and that the H5N1 viral protein PA can downregulate the expression of SAMHD1 by affecting SAMHD1 transcriptional promoter activity. We also found that SAMHD1's ability to restrict H5N1 is related to phosphorylation at 592-tyrosine.
    CONCLUSIONS: In conclusion, we found that SAMHD1 may affect the replication of IAVs as a host restriction factor and be countered by PA. Furthermore, SAMHD1 may be a potential target for developing antiviral drugs.
    Keywords:  H5N1; Host restriction factor; Influenza virus; PA; SAMHD1
    DOI:  https://doi.org/10.1186/s12985-024-02295-0
  6. Cell Death Dis. 2024 Jan 30. 15(1): 100
    Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.
    Stefanie M Bader, James P Cooney, Reet Bhandari, Liana Mackiewicz, Merle Dayton, Dylan Sheerin, Smitha Rose Georgy, James M Murphy, Kathryn C Davidson, Cody C Allison, Marc Pellegrini, Marcel Doerflinger.
      Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.
    DOI:  https://doi.org/10.1038/s41419-024-06471-6
  7. Curr Cancer Drug Targets. 2024 Jan 26.
    Effect of HPV Oncoprotein on Carbohydrate and Lipid Metabolism in Tumor Cells.
    Biqing Chen, Yichao Wang, Yishi Wu, Tianmin Xu.
      High-risk HPV infection accounts for 99.7% of cervical cancer, over 90% of anal cancer, 50% of head and neck cancers, 40% of vulvar cancer, and some cases of vaginal and penile cancer, contributing to approximately 5% of cancers worldwide. The development of cancer is a complex, multi-step process characterized by dysregulation of signaling pathways and alterations in metabolic pathways. Extensive research has demonstrated that metabolic reprogramming plays a key role in the progression of various cancers, such as cervical, head and neck, bladder, and prostate cancers, providing the material and energy foundation for rapid proliferation and migration of cancer cells. Metabolic reprogramming of tumor cells allows for the rapid generation of ATP, aiding in meeting the high energy demands of HPV-related cancer cell proliferation. The interaction between Human Papillomavirus (HPV) and its associated cancers has become a recent focus of investigation. The impact of HPV on cellular metabolism has emerged as an emerging research topic. A significant body of research has shown that HPV influences relevant metabolic signaling pathways, leading to cellular metabolic alterations. Exploring the underlying mechanisms may facilitate the discovery of biomarkers for diagnosis and treatment of HPV-associated diseases. In this review, we introduced the molecular structure of HPV and its replication process, discussed the diseases associated with HPV infection, described the energy metabolism of normal cells, highlighted the metabolic features of tumor cells, and provided an overview of recent advances in potential therapeutic targets that act on cellular metabolism. We discussed the potential mechanisms underlying these changes. This article aims to elucidate the role of Human Papillomavirus (HPV) in reshaping cellular metabolism and the application of metabolic changes in the research of related diseases. Targeting cancer metabolism may serve as an effective strategy to support traditional cancer treatments, as metabolic reprogramming is crucial for malignant transformation in cancer.
    Keywords:  Carbohydrate metabolism; HPV.; cervical cancer; lipid metabolism
    DOI:  https://doi.org/10.2174/0115680096266981231215111109
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