bims-mevinf 2023-05-21 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–05–21
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Rewiring of the Host Cell Metabolome and Lipidome during Lytic Gammaherpesvirus Infection Is Essential for Infectious-Virus Production.
Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication.
Glycolytic stress deteriorates 229E virulence to improve host defense response.
Single-Cell Transcriptome Atlas of Newcastle Disease Virus in Chickens Both In Vitro and In Vivo.
Respiratory Syncytial Virus Matrix Protein Is Sufficient and Necessary to Remodel Host Mitochondria in Infection.
Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells.
Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat.
Integrating metabolomics and network pharmacology to assess the effects of quercetin on lung inflammatory injury induced by human respiratory syncytial virus.
Metabolomics in rare minnow (Gobiocypris rarus) after infection by attenuated and virulent grass carp reovirus genotype Ⅱ.
Duox mediated ROS production inhibited WSSV replication in Eriocheir sinensis under short-term nitrite stress.
Uric acid metabolism promotes apoptosis against Bombyx mori nucleopolyhedrovirus in silkworm, Bombyx mori.

J Virol. 2023 May 16. e0050623

Rewiring of the Host Cell Metabolome and Lipidome during Lytic Gammaherpesvirus Infection Is Essential for Infectious-Virus Production.

Sarah A Clark, Angie Vazquez, Kelsey Furiya, Madeleine K Splattstoesser, Abdullah K Bashmail, Haleigh Schwartz, Makaiya Russell, Shun-Je Bhark, Osvaldo K Moreno, Morgan McGovern, Eric R Owsley, Timothy A Nelson, Erica L Sanchez, Tracie Delgado.

  Oncogenic virus infections are estimated to cause ~15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors. IMPORTANCE Viruses are intracellular parasites which lack their own metabolism, so they must hijack host cell metabolic machinery in order to increase the production of energy, proteins, fats, and genetic material necessary to replicate. Using murine herpesvirus 68 (MHV-68) as a model system to understand how similar human gammaherpesviruses cause cancer, we profiled the metabolic changes that occur during lytic MHV-68 infection and replication. We found that MHV-68 infection of host cells increases glucose, glutamine, lipid, and nucleotide metabolic pathways. We also showed inhibition or starvation of glucose, glutamine, or lipid metabolic pathways results in an inhibition of virus production. Ultimately, targeting changes in host cell metabolism due to viral infection can be used to treat gammaherpesvirus-induced cancers and infections in humans.

Keywords:  EBV; Epstein-Barr virus; KSHV; Kaposi’s sarcoma herpesvirus; MHV-68; gammaherpesvirus; herpesvirus; lipidomics; metabolism; metabolomics; murine herpesvirus 68

DOI:  https://doi.org/10.1128/jvi.00506-23
Cell Commun Signal. 2023 May 19. 21(1): 114

Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication.

Gloria Stoyanova, Sidra Jabeen, Joselyn Landazuri Vinueza, Sounak Ghosh Roy, Richard A Lockshin, Zahra Zakeri.

   BACKGROUND: Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.
METHODS: We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.
RESULTS: Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.
CONCLUSIONS: We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.

Keywords:  Atorvastatin; Autophagy; Lipid droplets; Statins; Viral replication; Zika virus

DOI:  https://doi.org/10.1186/s12964-022-01026-8
Microbes Infect. 2023 May 11. pii: S1286-4579(23)00053-9. [Epub ahead of print] 105150

Glycolytic stress deteriorates 229E virulence to improve host defense response.

Neha Kaushik, Paritosh Patel, Pradeep Bhartiya, Yungoh Shin, June Hyun Kim, Eun Ha Choi, Nagendra Kumar Kaushik.

  Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and readily adjust to harsh environments. Coronavirus stimulates glycolysis, weakens mitochondrial activity, and impairs infected cells. In this study, we investigated the efficacy of 2-DG in inhibiting coronavirus-induced metabolic processes and antiviral host defense systems, which have not been explored so far. 2-Deoxy-d-glucose (2-DG), a molecule restricting substrate availability, has recently gained attention as a potential antiviral drug. The results revealed that 229E human coronavirus promoted glycolysis, producing a significant increase in the concentration of fluorescent 2-NBDG, a glucose analog, particularly in the infected host cells. The addition of 2-DG decreased its viral replication and suppressed infection-induced cell death and cytopathic effects, thereby improving the antiviral host defense response. It was also observed that administration of low doses of 2-DG inhibited glucose uptake, indicating that 2-DG consumption in virus-infected host cells was mediated by high-affinity glucose transporters, whose levels were amplified upon coronavirus infection. Our findings indicated that 2-DG could be a potential drug to improve the host defense system in coronavirus-infected cells.

Keywords:  antimetabolite; host antiviral response; metabolic reprogramming; spike protein reduction; viral inactivation

DOI:  https://doi.org/10.1016/j.micinf.2023.105150
Microbiol Spectr. 2023 May 16. e0512122

Single-Cell Transcriptome Atlas of Newcastle Disease Virus in Chickens Both In Vitro and In Vivo.

Weiwei Liu, Zejun Xu, Yafeng Qiu, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Ying Liao, Xiufan Liu, Chan Ding.

  Newcastle disease virus (NDV) is an avian paramyxovirus that causes major economic losses to the poultry industry around the world, with NDV pathogenicity varying due to strain virulence differences. However, the impacts of intracellular viral replication and the heterogeneity of host responses among cell types are unknown. Here, we investigated the heterogeneity of lung tissue cells in response to NDV infection in vivo and that of the chicken embryo fibroblast cell line DF-1 in response to NDV infection in vitro using single-cell RNA sequencing. We characterized the NDV target cell types in the chicken lung at the single-cell transcriptome level and classified cells into five known and two unknown cell types. The five known cell types are the targets of NDV in the lungs with virus RNA detected. Different paths of infection in the putative trajectories of NDV infection were distinguished between in vivo and in vitro, or between virulent Herts/33 strain and nonvirulent LaSota strain. Gene expression patterns and the interferon (IFN) response in different putative trajectories were demonstrated. IFN responses were elevated in vivo, especially in myeloid and endothelial cells. We distinguished the virus-infected and non-infected cells, and the Toll-like receptor signaling pathway was the main pathway after virus infection. Cell-cell communication analysis revealed the potential cell surface receptor-ligand of NDV. Our data provide a rich resource for understanding NDV pathogenesis and open the way to interventions specifically targeting infected cells. IMPORTANCE Newcastle disease virus (NDV) is an avian paramyxovirus that causes major economic losses to the poultry industry around the world, with NDV pathogenicity varying due to strain virulence differences. However, the impacts of intracellular viral replication and the heterogeneity of host responses among cell types are unknown. Here, we investigated the heterogeneity of lung tissue cells in response to NDV infection in vivo and that of the chicken embryo fibroblast cell line DF-1 in response to NDV infection in vitro using single-cell RNA sequencing. Our results open the way to interventions specifically targeting infected cells, suggest principles of virus-host interactions applicable to NDV and other similar pathogens, and highlight the potential for simultaneous single-cell measurements of both host and viral transcriptomes for delineating a comprehensive map of infection in vitro and in vivo. Therefore, this study can be a useful resource for the further investigation and understanding of NDV.

Keywords:  Newcastle disease virus; chicken; interferon response; single cell; transcript

DOI:  https://doi.org/10.1128/spectrum.05121-22
Cells. 2023 05 04. pii: 1311. [Epub ahead of print]12(9):

Respiratory Syncytial Virus Matrix Protein Is Sufficient and Necessary to Remodel Host Mitochondria in Infection.

MengJie Hu, Marie A Bogoyevitch, David A Jans.

  Although respiratory syncytial virus (RSV) is the most common cause of respiratory infection in infants, immunosuppressed adults and the elderly worldwide, there is no licensed RSV vaccine or widely applicable antiviral therapeutics We previously reported a staged redistribution of mitochondria with compromised respiratory activities and increased reactive oxygen species (ROS) generation during RSV infection. Here, we show for the first time that the RSV matrix protein (M) is sufficient and necessary to induce these effects. Ectopically expressed M, but not other RSV proteins, was able to induce mitochondrial perinuclear clustering, inhibition of mitochondrial respiration, loss of mitochondrial membrane potential (Δψm), and enhanced generation of mitochondrial ROS (mtROS) in infection. Truncation and mutagenic analysis revealed that the central nucleic acid-binding domain of M is essential for the effects on host mitochondria, with arginine/lysine residues 170/172 being critically important. Recombinant RSV carrying the arginine/lysine mutations in M was unable to elicit effects on host mitochondria. Further, wild-type but not mutant RSV was found to inhibit the mRNA expression of genes encoding mitochondrial proteins, including Complex I subunits. Importantly, the RSV mutant was impaired in virus production, underlining the importance of M-dependent effects on mitochondria to RSV infection. Together, our results highlight M's unique ability to remodel host cell mitochondria and its critical role in RSV infection, representing a novel, potential target for future anti-RSV strategies.

Keywords:  RSV infection; RSV matrix protein (M); host cell mitochondria; respiratory syncytial virus (RSV)

DOI:  https://doi.org/10.3390/cells12091311
Biomolecules. 2023 Apr 21. pii: 714. [Epub ahead of print]13(4):

Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells.

Olga N Ivanova, George S Krasnov, Anastasiya V Snezhkina, Anna V Kudryavtseva, Vyacheslav S Fedorov, Natalia F Zakirova, Michail V Golikov, Sergey N Kochetkov, Birke Bartosch, Vladimir T Valuev-Elliston, Alexander V Ivanov.

  Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted. Here, we present a transcriptomic analysis of the gene expression of various redox systems and related metabolic processes, such as polyamine and proline metabolism and the urea cycle in Huh7.5 hepatoma cells and the HepaRG liver progenitor cell line, that are widely used in hepatitis research. In addition, changes in response to the activation of polyamine catabolism that contribute to oxidative stress were studied. In particular, differences in the gene expression of various ROS-producing and ROS-neutralizing proteins, the enzymes of polyamine metabolisms and proline and urea cycles, as well as calcium ion transporters between cell lines, are shown. The data obtained are important for understanding the redox biology of viral hepatitis and elucidating the influence of the laboratory models used.

Keywords:  HepaRG; antioxidant enzymes; polyamines; proline metabolism; reactive oxygen species; urea cycle

DOI:  https://doi.org/10.3390/biom13040714
Int J Mol Sci. 2023 Apr 27. pii: 7947. [Epub ahead of print]24(9):

Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat.

Giusi Ianiro, Veronica D'Ezio, Ludovica Carpinelli, Cecilia Casella, Maria Carmela Bonaccorsi di Patti, Luigi Rosa, Piera Valenti, Marco Colasanti, Giovanni Musci, Antimo Cutone, Tiziana Persichini.

  The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc- cystine/glutamate antiporter which, in turn, can trigger glutamate-mediated excitotoxicity. Here, we present data on the efficacy of bovine Lactoferrin (bLf), both in its native (Nat-bLf) and iron-saturated (Holo-bLf) forms, in counteracting oxidative stress in U373 human astroglial cells constitutively expressing the viral protein (U373-Tat). Our results show that, dependent on iron saturation, both Nat-bLf and Holo-bLf can boost host antioxidant response by up-regulating System Xc- and the cell iron exporter Ferroportin via the Nuclear factor erythroid 2-related factor (Nrf2) pathway, thus reducing Reactive Oxygen Species (ROS)-mediated lipid peroxidation and DNA damage in astrocytes. In U373-Tat cells, both forms of bLf restore the physiological internalization of Transferrin (Tf) Receptor 1, the molecular gate for Tf-bound iron uptake. The involvement of astrocytic antioxidant response in Tat-mediated neurotoxicity was evaluated in co-cultures of U373-Tat with human neuronal SH-SY5Y cells. The results show that the Holo-bLf exacerbates Tat-induced excitotoxicity on SH-SY5Y, which is directly dependent on System-Xc- upregulation, thus highlighting the mechanistic role of iron in the biological activities of the glycoprotein.

Keywords:  HIV-1 Tat; Lactoferrin; Nrf-2; System Xc−; astrocytes; iron saturation; neurotoxicity; oxidative stress

DOI:  https://doi.org/10.3390/ijms24097947
Sci Rep. 2023 May 17. 13(1): 8051

Integrating metabolomics and network pharmacology to assess the effects of quercetin on lung inflammatory injury induced by human respiratory syncytial virus.

Ya-Lei Sun, Pei-Pei Zhao, Cheng-Bi Zhu, Ming-Chen Jiang, Xin-Min Li, Jia-Lei Tao, Chan-Chan Hu, Bin Yuan.

Quercetin (QR) has significant anti-respiratory syncytial virus (RSV) effects. However, its therapeutic mechanism has not been thoroughly explored. In this study, a lung inflammatory injury model caused by RSV was established in mice. Untargeted lung tissue metabolomics was used to identify differential metabolites and metabolic pathways. Network pharmacology was used to predict potential therapeutic targets of QR and analyze biological functions and pathways modulated by QR. By overlapping the results of the metabolomics and the network pharmacology analyses, the common targets of QR that were likely to be involved in the amelioration of RSV-induced lung inflammatory injury by QR were identified. Metabolomics analysis identified 52 differential metabolites and 244 corresponding targets, while network pharmacology analysis identified 126 potential targets of QR. By intersecting these 244 targets with the 126 targets, hypoxanthine-guanine phosphoribosyltransferase (HPRT1), thymidine phosphorylase (TYMP), lactoperoxidase (LPO), myeloperoxidase (MPO), and cytochrome P450 19A1 (CYP19A1) were identified as the common targets. The key targets, HPRT1, TYMP, LPO, and MPO, were components of purine metabolic pathways. The present study demonstrated that QR effectively ameliorated RSV-induced lung inflammatory injury in the established mouse model. Combining metabolomics and network pharmacology showed that the anti-RSV effect of QR was closely associated with purine metabolism pathways.

DOI: https://doi.org/10.1038/s41598-023-35272-8
Fish Shellfish Immunol. 2023 May 17. pii: S1050-4648(23)00326-1. [Epub ahead of print] 108840

Metabolomics in rare minnow (Gobiocypris rarus) after infection by attenuated and virulent grass carp reovirus genotype Ⅱ.

Jie Ma, Chen Xu, Yong Zhou, Nan Jiang, Mingyang Xue, Jiajia Cao, Shuang Li, Yuding Fan.

  Grass carp reovirus genotype Ⅱ (GCRV Ⅱ) causes hemorrhagic disease in a variety fish, seriously affecting the aquaculture industry in China. However, the pathogenesis of GCRV Ⅱ is unclear. Rare minnow is an ideal model organism to study the pathogenesis of GCRV Ⅱ. Herein, we applied liquid chromatography-tandem mass spectrometry metabolomics to investigate metabolic responses in the spleen and hepatopancreas of rare minnow injected with virulent GCRV Ⅱ isolate DY197 and attenuated isolate QJ205. Results indicated that marked metabolic changes were identified in both the spleen and hepatopancreas after GCRV Ⅱ infection, and the virulent DY197 strain induced more significantly different metabolites (SDMs) than the attenuated QJ205 strain. Moreover, most SDMs were downregulated in the spleen and tend to be upregulated in hepatopancreas. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that tissue-specific metabolic responses were identified after viruses infection, and the virulent DY197 strain induced more SDMs involved in amino acid metabolism in the spleen, especially the tryptophan metabolism, cysteine and methionine metabolism, which were essential for immune regulation in host; Meanwhile, nucleotide metabolism, protein synthesis and metabolism related pathways were enriched in the hepatopancreas by both virulent and attenuated strains. Our findings revealed the large scale metabolic alterations in rare minnow in response to attenuated and virulent GCRV Ⅱ infection, which will lead to a better understanding of the pathogenesis of viruses and host-pathogens interactions.

Keywords:  Gobiocypris rarus; Grass carp reovirus; Hepatopancreas; Metabolomics; Rare minnow; Spleen

DOI:  https://doi.org/10.1016/j.fsi.2023.108840
Aquat Toxicol. 2023 May 13. pii: S0166-445X(23)00178-9. [Epub ahead of print]260 106575

Duox mediated ROS production inhibited WSSV replication in Eriocheir sinensis under short-term nitrite stress.

Rui Jia, Xiaoling Dai, Yanfang Li, Xintong Yang, Xiuwen Min, Derun Quan, Peng Liu, Xin Huang, Jiachun Ge, Qian Ren.

  Nitrite stress and white spot syndrome virus (WSSV) infection are major problems threatening the sustainable and healthy development of Eriocheir sinensis. Some studies have found that nitrite stress can lead to the production of reactive oxygen species (ROS), whereas synthetic ROS plays a vital role in the signaling pathway. However, whether nitrite stress influences the infection of crabs by WSSV remains unclear. NADPH oxidases, including NOX1-5 and Duox1-2, are important for ROS production. In the present study, a novel Duox gene (designated as EsDuox) was identified from E. sinensis. The studies found that nitrite stress could increase the expression of EsDuox during WSSV infection and decrease the transcription of the WSSV envelope protein VP28. Moreover, nitrite stress could increase the production of ROS, and the synthesis of ROS relied on EsDuox. These results indicated a potential "nitrite stress-Duox activation-ROS production" pathway that plays a negative role in WSSV infection in E. sinensis. Further studies found that nitrite stress and EsDuox could promote the expression of EsDorsal transcriptional factor and antimicrobial peptides (AMPs) during WSSV infection. Moreover, the synthesis of AMPs was positively regulated by EsDorsal in the process of WSSV infection under nitrite stress. Furthermore, EsDorsal played an inhibitory role in the replication of WSSV under nitrite stress. Our study reveals a new pathway for "nitrite stress-Duox activation-ROS production-Dorsal activation-AMP synthesis" that is involved in the defense against WSSV infection in E. sinensis during short-term nitrite stress.

Keywords:  Antimicrobial peptides; Duox; Eriocheir sinensis; Nitrite stress; ROS; WSSV

DOI:  https://doi.org/10.1016/j.aquatox.2023.106575
Insect Mol Biol. 2023 May 20.

Uric acid metabolism promotes apoptosis against Bombyx mori nucleopolyhedrovirus in silkworm, Bombyx mori.

Zhi-Hao Su, Jun-Li Lv, Qi Ou, Zi-Qin Zhao, Kai-Yi Zheng, Xiao-Ying Zhang, Wen-Qing Lai, Xue-Yang Wang, Ming-Jie Deng, Mu-Wang Li.

  The white epidermis of silkworms is due to the accumulation of uric acid crystals. Abnormal silkworm uric acid metabolism decreases uric acid production, leading to a transparent or translucent phenotype. The oily silkworm op50 is a mutant strain with a highly transparent epidermis derived from the p50 strain. It shows more susceptibility to Bombyx mori nucleopolyhedrovirus (BmNPV) infection than the wild type; however, the underlying mechanism is unknown. This study analysed the changes in 34 metabolites in p50 and op50 at different times following BmNPV infection based on comparative metabolomics. The differential metabolites were mainly clustered in six metabolic pathways. Of these, the uric acid pathway was identified as critical for resistance in silkworms, as feeding with inosine significantly enhanced larval resistance compared to other metabolites and modulated other metabolic pathways. Additionally, the increased level of resistance to BmNPV in inosine-fed silkworms was associated with the regulation of apoptosis, which is mediated by the reactive oxygen species produced during uric acid synthesis. Furthermore, feeding the industrial strain Jingsong (JS) with inosine significantly increased the level of larval resistance to BmNPV, indicating its potential application in controlling the virus in sericulture. These results lay the foundation for clarifying the resistance mechanism of silkworms to BmNPV and provide new strategies and methods for the biological control of pests.

Keywords:  BmNPV; Bombyx mori; oily silkworm; resistance mechanism; uric acid metabolism

DOI:  https://doi.org/10.1111/imb.12850