bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2023–12–03
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance.
  2. A comparative NMR-based metabolomics study of lung parenchyma of severe COVID-19 patients.
  3. Expression of SARS-CoV-2 Nonstructural Proteins 3 and 4 Can Tune the Unfolded Protein Response in Cell Culture.
  4. Role of immunometabolism during congenital cytomegalovirus infection.
  5. The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
  6. Metabolomic profiling of Marek's disease virus infection in host cell based on untargeted LC-MS.
  7. Sphingomyelin synthase 1 supports two steps of rubella virus life cycle.
  1. J Virol. 2023 Nov 27. e0127223
    Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance.
    Luxin Pei, Kirsten E Overdahl, John P Shannon, Katherine M Hornick, Alan K Jarmusch, Heather D Hickman.
       IMPORTANCE: Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur in vivo during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.
    Keywords:  immune response; metabolism; poxvirus
    DOI:  https://doi.org/10.1128/jvi.01272-23
  2. Front Mol Biosci. 2023 ;10 1295216
    A comparative NMR-based metabolomics study of lung parenchyma of severe COVID-19 patients.
    Joaquín I Hurtado, Andrés López-Radcenco, José Luis Izquierdo-García, Fernando Rodríguez, Guillermo Moyna, Gonzalo Greif, Nicolás Nin.
      COVID-19 was the most significant infectious-agent-related cause of death in the 2020-2021 period. On average, over 60% of those admitted to ICU facilities with this disease died across the globe. In severe cases, COVID-19 leads to respiratory and systemic compromise, including pneumonia-like symptoms, acute respiratory distress syndrome, and multiorgan failure. While the upper respiratory tract and lungs are the principal sites of infection and injury, most studies on the metabolic signatures in COVID-19 patients have been carried out on serum and plasma samples. In this report we attempt to characterize the metabolome of lung parenchyma extracts from fatal COVID-19 cases and compare them with that from other respiratory diseases. Our findings indicate that the metabolomic profiles from fatal COVID-19 and non-COVID-19 cases are markedly different, with the former being the result of increased lactate and amino acid metabolism, altered energy pathways, oxidative stress, and inflammatory response. Overall, these findings provide additional insights into the pathophysiology of COVID-19 that could lead to the development of targeted therapies for the treatment of severe cases of the disease, and further highlight the potential of metabolomic approaches in COVID-19 research.
    Keywords:  COVID-19; ICU patients; NMR-based metabolomics; biomarkers; lung parenchyma
    DOI:  https://doi.org/10.3389/fmolb.2023.1295216
  3. J Proteome Res. 2023 Dec 01.
    Expression of SARS-CoV-2 Nonstructural Proteins 3 and 4 Can Tune the Unfolded Protein Response in Cell Culture.
    Jonathan P Davies, Athira Sivadas, Katherine R Keller, Brynn K Roman, Richard J H Wojcikiewicz, Lars Plate.
      Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through the activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and increasing protein folding capacity. While CoV nonstructural proteins (nsps) are essential for infection, little is known about the role of nsps in modulating the UPR. We characterized the impact of overexpression of SARS-CoV-2 nsp4, a key driver of replication, on the UPR in cell culture using quantitative proteomics to sensitively detect pathway-wide upregulation of effector proteins. We find that nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found that an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological ATF6 activation. To determine how nsp3.1 and nsp4 tune the UPR, their coexpression demonstrated that nsp3.1 suppresses nsp4-mediated PERK, but not ATF6 activation. Reanalysis of SARS-CoV-2 infection proteomics data revealed time-dependent activation of PERK targets early in infection, which subsequently fades. This temporal regulation suggests a role for nsp3 and nsp4 in tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic activation. This work furthers our understanding of CoV-host proteostasis interactions and highlights the power of proteomic methods for systems-level analysis of the UPR.
    Keywords:  ATF6; PERK; coronavirus; nonstructural protein; proteomics; stress response
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00600
  4. Immunometabolism (Cobham). 2023 Oct;5(4): e00034
    Role of immunometabolism during congenital cytomegalovirus infection.
    Kevin J Zwezdaryk, Amitinder Kaur.
      Cytomegalovirus (CMV) is a master manipulator of host metabolic pathways. The impact of CMV metabolic rewiring during congenital CMV on immune function is unknown. CMV infection can directly alter glycolytic and oxidative phosphorylation pathways in infected cells. Recent data suggests CMV may alter metabolism in uninfected neighboring cells. In this mini review, we discuss how CMV infection may impact immune function through metabolic pathways. We discuss how immune cells differ between maternal and decidual compartments and how altered immunometabolism may contribute to congenital infections.
    Keywords:  congenital cytomegalovirus; immunometabolism; placenta
    DOI:  https://doi.org/10.1097/IN9.0000000000000034
  5. Nat Commun. 2023 Nov 30. 14(1): 7889
    The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
    Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh.
      Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.
    DOI:  https://doi.org/10.1038/s41467-023-43635-y
  6. Front Microbiol. 2023 ;14 1270762
    Metabolomic profiling of Marek's disease virus infection in host cell based on untargeted LC-MS.
    Qingsen Wang, Bin Shi, Guifu Yang, Xueying Zhu, Hongxia Shao, Kun Qian, Jianqiang Ye, Aijian Qin.
      Marek's disease (MD) caused by Marek's disease virus (MDV), poses a serious threat to the poultry industry by inducing neurological disease and malignant lymphoma in infected chickens. However, the underlying mechanisms how MDV disrupts host cells and causes damage still remain elusive. Recently, the application of metabolomics has shown great potential for uncovering the complex mechanisms during virus-host interactions. In this study, chicken embryo fibroblasts (CEFs) infected with MDV were subjected to ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) and multivariate statistical analysis. The results showed that 261 metabolites were significantly altered upon MDV infection, with most changes occurring in amino acid metabolism, energy metabolism, nucleotide metabolism, and lipid metabolism. Notably, MDV infection induces an up-regulation of amino acids in host cells during the early stages of infection to provide the energy and intermediary metabolites necessary for efficient multiplication of its own replication. Taken together, these data not only hold promise in identifying the biochemical molecules utilized by MDV replication in host cells, but also provides a new insight into understanding MDV-host interactions.
    Keywords:  CEFs; LC-MS; Marek’s disease virus; amino acid; metabolites; the TCA cycle
    DOI:  https://doi.org/10.3389/fmicb.2023.1270762
  7. iScience. 2023 Nov 17. 26(11): 108267
    Sphingomyelin synthase 1 supports two steps of rubella virus life cycle.
    Mayuko Yagi, Minami Hama, Sayaka Ichii, Yurie Nakashima, Daiki Kanbayashi, Takako Kurata, Kosuke Yusa, Jun Komano.
      Our knowledge of the regulatory mechanisms that govern the replication of the rubella virus (RV) in human cells is limited. To gain insight into the host-pathogen interaction, we conducted a loss-of-function screening using the CRISPR-Cas9 system in the human placenta-derived JAR cells. We identified sphingomyelin synthase 1 (SGMS1 or SMS1) as a susceptibility factor for RV infection. Genetic knockout of SGMS1 rendered JAR cells resistant to infection by RV. The re-introduction of SGMS1 restored cellular susceptibility to RV infection. The restricted step of RV infection was post-endocytosis processes associated with the endosomal acidification. In the late phase of the RV replication cycle, the maintenance of viral persistence was disrupted, partly due to the attenuated viral gene expression. Our results shed light on the unique regulation of RV replication by a host factor during the early and late phases of viral life cycle.
    Keywords:  Molecular biology; Virology
    DOI:  https://doi.org/10.1016/j.isci.2023.108267
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