bims-mevinf 2023-08-20 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–08–20
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Metabolomic analysis of pig spleen reveals African swine fever virus infection increased acylcarnitine levels to facilitate viral replication.
Porcine reproductive and respiratory syndrome virus-mediated lactate facilitates virus replication by targeting MAVS.
Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation.
Intracellular Iron Accumulation Induces Inflammatory and Oxidative Status of the Host After Japanese Encephalitis Viral Infection.
Critical role for ribonucleoside-diphosphate reductase subunit M2 in ALV-J-induced activation of Wnt/β-catenin signaling via interaction with P27.
The metabolic consequences of HIV/TB co-infection.
Porcine reproductive and respiratory syndrome virus upregulates SMPDL3B to promote viral replication by modulating lipid metabolism.
Hypoxia dampens innate immune signalling at early time points and increases Zika virus RNA levels in iPSC-derived macrophages.
Metabolomics-directed nanotechnology in viral diseases management: COVID-19 a case study.
Single-cell RNA sequencing reveals characteristics of myeloid cells in pulmonary post-acute sequelae of SARS-CoV-2.
Role of lysosomes in HSV-induced pathogenesis.

J Virol. 2023 Aug 15. e0058623

Metabolomic analysis of pig spleen reveals African swine fever virus infection increased acylcarnitine levels to facilitate viral replication.

Xing Yang, Xintian Bie, Huanan Liu, Xijuan Shi, Dajun Zhang, DengShuai Zhao, Yu Hao, Jinke Yang, Wenqian Yan, Guohui Chen, Lingling Chen, Zixiang Zhu, Fan Yang, Xusheng Ma, Xiangtao Liu, Haixue Zheng, Keshan Zhang.

  African swine fever (ASF) is a devastating disease caused by the African swine fever virus (ASFV) that adversely affects the pig industry. The spleen is the main target organ of ASFV; however, the function of metabolites in the spleen during ASFV infection is yet to be investigated. To define the metabolic changes in the spleen after ASFV infection, untargeted and targeted metabolomics analyses of spleens from ASFV-infected pigs were conducted. Untargeted metabolomics analysis revealed 540 metabolites with significant differential levels. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these metabolites were mainly enriched in metabolic pathways, including nucleotide metabolism, purine metabolism, arginine biosynthesis, and neuroactive ligand-receptor interaction. Moreover, 134 of 540 metabolites quantified by targeted metabolomics analysis had differential levels and were enriched in metabolic pathways such as the biosynthesis of cofactors, ABC transporters, and biosynthesis of amino acids. Furthermore, coalition analysis of untargeted and targeted metabolomics data revealed that the levels of acylcarnitines, which are intermediates of fatty acid β-oxidation, were significantly increased in ASFV-infected spleens compared with those in the uninfected spleens. Moreover, inhibiting fatty acid β-oxidation significantly reduced ASFV replication, indicating that fatty acid β-oxidation is essential for this process. To our knowledge, this is the first report presenting the metabolite profiles of ASFV-infected pigs. This study revealed a new mechanism of ASFV-mediated regulation of host metabolism. These findings provide new insights into the pathogenic mechanisms of ASFV, which will benefit the development of target drugs for ASFV replication. IMPORTANCE African swine fever virus, the only member of the Asfarviridae family, relies on hijacking host metabolism to meet the demand for self-replication. However, the change in host metabolism after African swine fever virus (ASFV) infection remains unknown. Here, we analyzed the metabolic changes in the pig spleen after ASFV infection for the first time. ASFV infection increased the levels of acylcarnitines. Inhibition of the production and metabolism of acylcarnitines inhibited ASFV replication. Acylcarnitines are the vital intermediates of fatty acid β-oxidation. This study highlights the critical role of fatty acid β-oxidation in ASFV infection, which may help identify target drugs to control African swine fever disease.

Keywords:  African swine fever virus; acyl-carnitines; fatty acid β-oxidation; metabolomics; spleen

DOI:  https://doi.org/10.1128/jvi.00586-23
Vet Microbiol. 2023 Aug 09. pii: S0378-1135(23)00198-0. [Epub ahead of print]284 109846

Porcine reproductive and respiratory syndrome virus-mediated lactate facilitates virus replication by targeting MAVS.

Lujie Zhang, Xing Liu, Jian Mao, Yangyang Sun, Yanni Gao, Juan Bai, Ping Jiang.

  Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important causative agents in the pig industry worldwide, causing reproductive failure in sows and respiratory problems in growing pigs. Glucose metabolism is a major pathway for energy production and interacts with many cellular processes, such as innate immunity response. It is unclear whether PRRSV infection can use the glucose metabolic pathway to generate immune escape in favor of viral replication. Here, we found that high glucose promotes PRRSV replication and glycolysis, and inhibits poly(I:C)-induced RLR signaling. Conversely, inhibition of the glycolysis pathway significantly promoted poly(I:C)-induced RLR signaling and inhibited PRRSV replication, suggesting that glycolysis promotes PRRSV replication by inhibiting interferon signaling. Furthermore, PRRSV promotes glycolysis to produce lactate, which acts as a key metabolite to promote viral replication by inhibiting RLR signaling by targeting MAVS. And the glycolytic inhibitors targeting HK2 and LDHA in glycolysis could inhibit PRRSV replication. Taken together, these findings suggested that PRRSV infection promotes glycolysis to produce lactate, which targets MAVS to inhibit RLR signaling and thus promote viral replication. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.

Keywords:  Glycolysis; Lactate; MAVS; PRRSV

DOI:  https://doi.org/10.1016/j.vetmic.2023.109846
PLoS Pathog. 2023 Aug 16. 19(8): e1011591

Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation.

Kazuyoshi Ohta, Masahiko Ito, Takeshi Chida, Kenji Nakashima, Satoshi Sakai, Yumi Kanegae, Hideya Kawasaki, Takuya Aoshima, Shuji Takabayashi, Hirotaka Takahashi, Kazuhito Kawata, Ikuo Shoji, Tatsuya Sawasaki, Takafumi Suda, Tetsuro Suzuki.

Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells.

DOI: https://doi.org/10.1371/journal.ppat.1011591
Mol Neurobiol. 2023 Aug 18.

Intracellular Iron Accumulation Induces Inflammatory and Oxidative Status of the Host After Japanese Encephalitis Viral Infection.

Gajendra Singh, Anjali Singh, Sanjay Mishra, Devendra Singh, Alok Kumar.

  The factors mitigating the microglia/macrophage activation and inflammatory damage in Japanese encephalitis (JE) virus infected CNS are still being ascertained. We aim to characterize the changes in iron transporter and iron storage proteins along with inflammatory and oxidative stress-mediated signaling during the JE viral infection. Cortical tissue samples from mice with JE viral infection were processed for biochemical, histological, and molecular analysis. Iron storage protein, i.e., ferritin, was found significantly increased post-JE viral infection, and iron accumulation was noted in cortical tissue. Key proinflammatory associated markers, such as TNF-α, IL-6, and its regulator TLR4, were found to be increased, while SOCS1 (anti-inflammatory regulator) transcription decreased with increased levels of oxidative stress markers NOX2-mediated NF-ΚB/p65 and protein carbonyl. Furthermore, it is noted that hepcidin level increased and ferroportin level decreased, and iron transporter gene expression got imbalanced after JE viral infection. This observation was further confirmed by deferoxamine (DFO) treatment to JE viral infection mice model, where the decline in hepcidin transcription level and iron load in cortical tissue of JE viral infected animals was noted. However, no change was found in the ferroportin level compared to JE viral infected animals. Together, these findings suggest that iron overload and hepcidin-ferroportin regulation are involved in JE viral infection disease pathologies and associated with the inflammatory and oxidative status of the host during infection.

Keywords:  Deferoxamine; Hepcidin-ferroportin regulation; Inflammation; Iron; Japanese encephalitis viral infection; NF-ΚB/p65; Oxidative stress; gp91phox (NADPH-oxidase/NOX2)

DOI:  https://doi.org/10.1007/s12035-023-03538-x
J Virol. 2023 Aug 15. e0026723

Critical role for ribonucleoside-diphosphate reductase subunit M2 in ALV-J-induced activation of Wnt/β-catenin signaling via interaction with P27.

Shuang Tang, Mei Leng, Chen Tan, Lin Zhu, Yanling Pang, Xinheng Zhang, Yung-Fu Chang, Wencheng Lin.

  Avian leukemia virus subgroup J (ALV-J) causes various diseases associated with tumor formation and decreased fertility and induced immunosuppressive disease, resulting in significant economic losses in the poultry industry globally. Virus usually exploits the host cellular machinery for their replication. Although there are increasing evidences for the cellular proteins involving viral replication, the interaction between ALV-J and host proteins leading to the pivotal steps of viral life cycle are still unclear. Here, we reported that ribonucleoside-diphosphate reductase subunit M2 (RRM2) plays a critical role during ALV-J infection by interacting with capsid protein P27 and activating Wnt/β-catenin signaling. We found that the expression of RRM2 is effectively increased during ALV-J infection, and that RRM2 facilitates ALV-J replication by interacting with viral capsid protein P27. Furthermore, ALV-J P27 activated Wnt/β-catenin signaling by promoting β-catenin entry into the nucleus, and RRM2 activated Wnt/β-catenin signaling by enhancing its phosphorylation at Ser18 during ALV-J infection. These data suggest that the upregulation of RRM2 expression by ALV-J infection favors viral replication in host cells via activating Wnt/β-catenin signaling. IMPORTANCE Our results revealed a novel mechanism by which RRM2 facilitates ALV-J growth. That is, the upregulation of RRM2 expression by ALV-J infection favors viral replication by interacting with capsid protein P27 and activating Wnt/β-catenin pathway in host cells. Furthermore, the phosphorylation of serine at position 18 of RRM2 was verified to be the important factor regulating the activation of Wnt/β-catenin signaling. This study provides insights for further studies of the molecular mechanism of ALV-J infection.

Keywords:  ALV-J; RRM2; Wnt/β-catenin signaling; replication

DOI:  https://doi.org/10.1128/jvi.00267-23
BMC Infect Dis. 2023 Aug 18. 23(1): 536

The metabolic consequences of HIV/TB co-infection.

Chandré Herbert, Laneke Luies, Du Toit Loots, Aurelia A Williams.

   BACKGROUND: The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis during co-infection of a host is well known. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/tuberculosis (TB) co-infection remain poorly understood. Furthermore, while anti-HIV treatments suppress viral replication, these therapeutics give rise to host metabolic disruption and adaptations beyond that induced by only infection or disease.
METHODS: In this study, the serum metabolic profiles of healthy controls, untreated HIV-negative TB-positive patients, untreated HIV/TB co-infected patients, and HIV/TB co-infected patients on antiretroviral therapy (ART), were measured using two-dimensional gas chromatography time-of-flight mass spectrometry. Since no global metabolic profile for HIV/TB co-infection and the effect of ART has been published to date, this pilot study aimed to elucidate the general areas of metabolism affected during such conditions.
RESULTS: HIV/TB co-infection induced significant changes to the host's lipid and protein metabolism, with additional microbial product translocation from the gut to the blood. The results suggest that HIV augments TB synergistically, at least in part, contributing to increased inflammation, oxidative stress, ART-induced mitochondrial damage, and its detrimental effects on gut health, which in turn, affects energy availability. ART reverses these trends to some extent in HIV/TB co-infected patients but not to that of healthy controls.
CONCLUSION: This study generated several new hypotheses that could direct future metabolic studies, which could be combined with other research techniques or methodologies to further elucidate the underlying mechanisms of these changes.

Keywords:  GCxGC-TOFMS; Gut microbiome; HIV/AIDS; HIV/TB co-infection; Metabolism; Metabolomics; Tuberculosis

DOI:  https://doi.org/10.1186/s12879-023-08505-4
iScience. 2023 Aug 18. 26(8): 107450

Porcine reproductive and respiratory syndrome virus upregulates SMPDL3B to promote viral replication by modulating lipid metabolism.

Huan-Huan Shen, Qin Zhao, Yi-Ping Wen, Rui Wu, Sen-Yan Du, Xiao-Bo Huang, Xin-Tian Wen, San-Jie Cao, Lei Zeng, Qi-Gui Yan.

  Porcine reproductive and respiratory syndrome virus (PRRSV) poses a severe threat to the health of pigs globally. Host factors play a critical role in PRRSV replication. Using PRRSV as a model for genome-scale CRISPR knockout (KO) screening, we identified a host factor critical to PRRSV infection: sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B). Our findings show that SMPDL3B restricted PRRSV attachment, entry, replication, and secretion and that its depletion significantly inhibited PRRSV proliferation, indicating that SMPDL3B plays a positive role in PRRSV replication. Our data also show that SMPDL3B deficiency resulted in an accumulation of intracellular lipid droplets (LDs). The expression level of key genes (ACC, SCD-1, and FASN) involved in lipogenesis was increased, whereas the fundamental lipolysis gene, ATGL, was inhibited when SMPDL3B was knocked down. Overall, our findings suggest that SMPDL3B deficiency can effectively inhibit viral infection through the modulation of lipid metabolism.

Keywords:  Biological sciences; Molecular biology; Molecular physiology; Virology

DOI:  https://doi.org/10.1016/j.isci.2023.107450
J Gen Virol. 2023 08;104(8):

Hypoxia dampens innate immune signalling at early time points and increases Zika virus RNA levels in iPSC-derived macrophages.

Mirjam Schilling, Alun Vaughan-Jackson, William James, Jane A McKeating.

  Type I interferons (IFNs) are the major host defence against viral infection and are induced following activation of cell surface or intracellular pattern recognition receptors, including retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs). All cellular processes are shaped by the microenvironment and one important factor is the local oxygen tension. The majority of published studies on IFN signalling are conducted under laboratory conditions of 18% oxygen (O2), that do not reflect the oxygen levels in most organs (1-5 % O2). We studied the effect of low oxygen on IFN induction and signalling in induced Pluripotent Stem Cell (iPSC)-derived macrophages as a model for tissue-resident macrophages and assessed the consequence for Zika virus (ZIKV) infection. Hypoxic conditions dampened the expression of interferon-stimulated genes (ISGs) following RLR stimulation or IFN treatment at early time points. RNA-sequencing and bio-informatic analysis uncovered several pathways including changes in transcription factor availability, the presence of HIF binding sites in promoter regions, and CpG content that may contribute to the reduced ISG expression. Hypoxic conditions increased the abundance of ZIKV RNA highlighting the importance of understanding how low oxygen conditions in the local microenvironment affect pathogen sensing and host defences.

Keywords:  HIF; IFN; ISGs; MX1; RIG-I; ZIKV; hypoxia; iPSC

DOI:  https://doi.org/10.1099/jgv.0.001885
Pharmacol Rep. 2023 Aug 16.

Metabolomics-directed nanotechnology in viral diseases management: COVID-19 a case study.

Marwa O El-Derany, Diana M F Hanna, John Youshia, Enas Elmowafy, Mohamed A Farag, Samar S Azab.

  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently regarded as the twenty-first century's plague accounting for coronavirus disease 2019 (COVID-19). Besides its reported symptoms affecting the respiratory tract, it was found to alter several metabolic pathways inside the body. Nanoparticles proved to combat viral infections including COVID-19 to demonstrate great success in developing vaccines based on mRNA technology. However, various types of nanoparticles can affect the host metabolome. Considering the increasing proportion of nano-based vaccines, this review compiles and analyses how COVID-19 and nanoparticles affect lipids, amino acids, and carbohydrates metabolism. A search was conducted on PubMed, ScienceDirect, Web of Science for available information on the interrelationship between metabolomics and immunity in the context of SARS-CoV-2 infection and the effect of nanoparticles on metabolite levels. It was clear that SARS-CoV-2 disrupted several pathways to ensure a sufficient supply of its building blocks to facilitate its replication. Such information can help in developing treatment strategies against viral infections and COVID-19 based on interventions that overcome these metabolic changes. Furthermore, it showed that even drug-free nanoparticles can exert an influence on biological systems as evidenced by metabolomics.

Keywords:  COVID-19; Metabolomics; Nanoparticles; SARS-CoV-2; Viral infections

DOI:  https://doi.org/10.1007/s43440-023-00517-w
bioRxiv. 2023 Aug 02. pii: 2023.07.31.551349. [Epub ahead of print]

Single-cell RNA sequencing reveals characteristics of myeloid cells in pulmonary post-acute sequelae of SARS-CoV-2.

Hyundong Yoon, Logan S Dean, Boonyanudh Jiyarom, Vedbar Khadka, Youping Deng, Vivek R Nerurukar, Dominic C Chow, Cecilia M Shikuma, Gehan Devendra, Youngil Koh, Juwon Park.

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequalae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, the dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown.
Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naïve to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14 + /CD16 + monocytes and dendritic cells) was increased in PPASC compared to controls. MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis- related ( VEGF , WNT , and SMAD ) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. In PPASC, we observed interactive VEGF ligand- receptor pairs among MLCs, and network modules in CD14 + (cluster 4) and CD16 + (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID- 19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS- CoV-2 naïve samples.
Conclusion: This study offers valuable insights into the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests their potential role as a driver of PPASC.

DOI: https://doi.org/10.1101/2023.07.31.551349
Future Microbiol. 2023 Aug 16.

Role of lysosomes in HSV-induced pathogenesis.

Jieqiong Ding, Liqiong Ding.

  HSV can evade host defenses and cause lifelong infection and severe illness. Lysosomes are catabolic organelles that play an important role in the regulation of cellular homeostasis. Lysosomal dysfunction and alterations in the process of autophagy have been identified in a variety of diseases, including HSV infection, and targeting lysosomes is a potential anti-HSV therapeutic strategy. This article reviews the role of lysosomes and lysosome-associated proteins in HSV infection, providing attractive targets and novel strategies for the treatment of HSV infection.

Keywords:  HSV; autophagy; hydrolases; lysosome; lysosome-associated membrane glycoproteins

DOI:  https://doi.org/10.2217/fmb-2023-0090