bims-mevinf 2023-04-02 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–04–02
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.
Host Cell Targets for Unconventional Antivirals against RNA Viruses.
Metabolomic and Proteomic Profiling of Porcine Intestinal Epithelial Cells Infected with Porcine Epidemic Diarrhea Virus.
Porcine reproductive and respiratory syndrome virus infection triggers autophagy via ER stress-induced calcium signaling to facilitate virus replication.
Astrocytes derived from neural progenitor cells are susceptible to Zika virus infection.
Influenza viral matrix 1 protein aggravates viral pathogenicity by inducing TLR4-mediated reactive oxygen species production and apoptotic cell death.
A single-cell atlas reveals shared and distinct immune responses and metabolic profiles in SARS-CoV-2 and HIV-1 infections.
An untargeted metabolomics investigation in liver of flaviviruses-infected mice.

Metabolomics. 2023 Mar 29. 19(4): 30

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.

Yao Lu, Shan Xu, Huan Sun, Jinjun Shan, Cunsi Shen, Jianjian Ji, Lili Lin, Jianya Xu, Linxiu Peng, Chen Dai, Tong Xie.

   INTRODUCTION: Human respiratory syncytial virus (HRSV) infection causes significant morbidity, and no effective treatments are currently available. Viral infections induce substantial metabolic changes in the infected cells to optimize viral production. Metabolites that reflect the interactions between host cells and viruses provided an opportunity to identify the pathways underlying severe infections.
OBJECTIVE: To better understand the metabolic changes caused by HRSV infection, we analyzed temporal metabolic profiling to provide novel targets for therapeutic strategies for inhaled HRSV infection.
METHODS: The epithelial cells and BALB/c mice were infected with HRSV. Protein and mRNA levels of inflammation factors were measured by using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Untargeted metabolomics, lipidomics and proteomics were performed using liquid chromatography coupled with mass spectrometry to profile the metabolic phenotypic alterations in HRSV infection.
RESULTS: In this study, we evaluated the inflammatory responses in vivo and in vitro and investigated the temporal metabolic rewiring of HRSV infection in epithelial cells. We combined metabolomics and proteomic analyses to demonstrate that the redox imbalance was further provoked by increasing glycolysis and anaplerotic reactions. These responses created an oxidant-rich microenvironment that elevated reactive oxygen species levels and exacerbated glutathione consumption.
CONCLUSION: These observations indicate that adjusting for metabolic events during a viral infection could represent a valuable approach for reshaping the outcome of infections.

Keywords:  Glutamine and glutamate metabolism; Human respiratory syncytial virus; Metabolic remodeling; Metabolomics

DOI:  https://doi.org/10.1007/s11306-023-01991-2
Viruses. 2023 Mar 17. pii: 776. [Epub ahead of print]15(3):

Host Cell Targets for Unconventional Antivirals against RNA Viruses.

Vicky C Roa-Linares, Manuela Escudero-Flórez, Miguel Vicente-Manzanares, Juan C Gallego-Gómez.

  The recent COVID-19 crisis has highlighted the importance of RNA-based viruses. The most prominent members of this group are SARS-CoV-2 (coronavirus), HIV (human immunodeficiency virus), EBOV (Ebola virus), DENV (dengue virus), HCV (hepatitis C virus), ZIKV (Zika virus), CHIKV (chikungunya virus), and influenza A virus. With the exception of retroviruses which produce reverse transcriptase, the majority of RNA viruses encode RNA-dependent RNA polymerases which do not include molecular proofreading tools, underlying the high mutation capacity of these viruses as they multiply in the host cells. Together with their ability to manipulate the immune system of the host in different ways, their high mutation frequency poses a challenge to develop effective and durable vaccination and/or treatments. Consequently, the use of antiviral targeting agents, while an important part of the therapeutic strategy against infection, may lead to the selection of drug-resistant variants. The crucial role of the host cell replicative and processing machinery is essential for the replicative cycle of the viruses and has driven attention to the potential use of drugs directed to the host machinery as therapeutic alternatives to treat viral infections. In this review, we discuss small molecules with antiviral effects that target cellular factors in different steps of the infectious cycle of many RNA viruses. We emphasize the repurposing of FDA-approved drugs with broad-spectrum antiviral activity. Finally, we postulate that the ferruginol analog (18-(phthalimide-2-yl) ferruginol) is a potential host-targeted antiviral.

Keywords:  RNA viruses; drug repositioning; host-targeted antivirals

DOI:  https://doi.org/10.3390/v15030776
Int J Mol Sci. 2023 Mar 07. pii: 5071. [Epub ahead of print]24(6):

Metabolomic and Proteomic Profiling of Porcine Intestinal Epithelial Cells Infected with Porcine Epidemic Diarrhea Virus.

Haifei Wang, Peng Hui, Yoshinobu Uemoto, Yueyun Ding, Zongjun Yin, Wenbin Bao.

  Porcine epidemic diarrhea virus (PEDV) infection results in severe epidemic diarrhea and the death of suckling pigs. Although new knowledge about the pathogenesis of PEDV has been improved, alterations in metabolic processes and the functional regulators involved in PEDV infection with host cells remain largely unknow. To identify cellular metabolites and proteins related to PEDV pathogenesis, we synergistically investigated the metabolome and proteome profiles of PEDV-infected porcine intestinal epithelial cells by liquid chromatography tandem mass spectrometry and isobaric tags for relative and absolute quantification techniques. We identified 522 differential metabolites in positive and negative ion modes and 295 differentially expressed proteins after PEDV infection. Pathways of cysteine and methionine metabolism, glycine, serine and threonine metabolism, and mineral absorption were significantly enriched by differential metabolites and differentially expressed proteins. The betaine-homocysteine S-methyltransferase (BHMT) was indicated as a potential regulator involved in these metabolic processes. We then knocked down the BHMT gene and observed that down-expression of BHMT obviously decreased copy numbers of PEDV and virus titers (p < 0.01). Our findings provide new insights into the metabolic and proteomic profiles in PEDV-infected host cells and contribute to our further understanding of PEDV pathogenesis.

Keywords:  metabolomics; porcine epidemic diarrhea virus; proteomics; virus replication

DOI:  https://doi.org/10.3390/ijms24065071
PLoS Pathog. 2023 Mar 27. 19(3): e1011295

Porcine reproductive and respiratory syndrome virus infection triggers autophagy via ER stress-induced calcium signaling to facilitate virus replication.

Feifei Diao, Chenlong Jiang, Yangyang Sun, Yanni Gao, Juan Bai, Hans Nauwynck, Xianwei Wang, Yuanqi Yang, Ping Jiang, Xing Liu.

Calcium (Ca2+), a ubiquitous second messenger, plays a crucial role in many cellular functions. Viruses often hijack Ca2+ signaling to facilitate viral processes such as entry, replication, assembly, and egress. Here, we report that infection by the swine arterivirus, porcine reproductive and respiratory syndrome virus (PRRSV), induces dysregulated Ca2+ homeostasis, subsequently activating calmodulin-dependent protein kinase-II (CaMKII) mediated autophagy, and thus fueling viral replication. Mechanically, PRRSV infection induces endoplasmic reticulum (ER) stress and forms a closed ER-plasma membrane (PM) contacts, resulting the opening of store operated calcium entry (SOCE) channel and causing the ER to take up extracellular Ca2+, which is then released into the cytoplasm by inositol trisphosphate receptor (IP3R) channel. Importantly, pharmacological inhibition of ER stress or CaMKII mediated autophagy blocks PRRSV replication. Notably, we show that PRRSV protein Nsp2 plays a dominant role in the PRRSV induced ER stress and autophagy, interacting with stromal interaction molecule 1 (STIM1) and the 78 kDa glucose-regulated protein 78 (GRP78). The interplay between PRRSV and cellular calcium signaling provides a novel potential approach to develop antivirals and therapeutics for the disease outbreaks.

DOI: https://doi.org/10.1371/journal.ppat.1011295
PLoS One. 2023 ;18(3): e0283429

Astrocytes derived from neural progenitor cells are susceptible to Zika virus infection.

Edson Iván Rubio-Hernández, Mauricio Comas-García, Miguel Angel Coronado-Ipiña, Mayra Colunga-Saucedo, Hilda Minerva González Sánchez, Claudia G Castillo.

Zika virus (ZIKV) was first isolated in 1947. From its isolation until 2007, symptoms of ZIKV-caused disease were limited (e.g., fever, hives, and headache); however, during the epidemic in Brazil in 2014, ZIKV infection caused Guillain-Barré syndrome in adults and microcephaly in fetuses and infants of women infected during pregnancy. The neurovirulence of ZIKV has been studied using neural progenitor cells (NPCs), brain organoids, neurons, and astrocytes. NPCs and astrocytes appear to be the most susceptible cells of the Central Nervous System to ZIKV infection. In this work, we aimed to develop a culture of astrocytes derived from a human NPC cell line. We analyze how ZIKV affects human astrocytes and demonstrate that 1) ZIKV infection reduces cell viability, increases the production of Reactive Oxygen Species (ROS), and results in high viral titers; 2) there are changes in the expression of genes that facilitate the entry of the virus into the cells; 3) there are changes in the expression of genes involved in the homeostasis of the glutamatergic system; and 4) there are ultrastructural changes in mitochondria and lipid droplets associated with production of virions. Our findings reveal new evidence of how ZIKV compromises astrocytic functionality, which may help understand the pathophysiology of ZIKV-associated congenital disease.

DOI: https://doi.org/10.1371/journal.pone.0283429
Cell Death Dis. 2023 Mar 30. 14(3): 228

Influenza viral matrix 1 protein aggravates viral pathogenicity by inducing TLR4-mediated reactive oxygen species production and apoptotic cell death.

Chang-Ung Kim, Dahwan Lim, Young Sang Kim, Bonsu Ku, Doo-Jin Kim.

Influenza virus is one of the most challenging viruses threating human health. Since infection with influenza virus triggers inflammatory responses and induces cell death, the molecular and cellular mechanisms by which the virus-infected cells undergo apoptotic and necrotic cell death have been widely studied. However, most of the studies have focused on the molecular events occurring in the cytosol and there is limited information on the physiological correlation between virus-induced cell death and the viral pathogenesis in vivo. In this study, we demonstrate that the influenza virus matrix 1 (M1) protein is released from virus-infected cells and triggers apoptotic cell death of lung epithelial and pulmonary immune cells, through the activation of Toll-like receptor 4 (TLR4) signaling. Treatment with M1 protein led to robust cellular inflammatory responses, such as the production of proinflammatory cytokines and cellular reactive oxygen species (ROS), and induction of cell death. When M1 protein was administered in vivo, it induced the activation of inflammatory responses and cell death in the lungs. Furthermore, the administration of M1 aggravated lung pathology and mortality of the virus-infected mice in a TLR4-dependent manner. These results demonstrate that M1 is an important pathogenic factor contributing to influenza virus pathogenicity by enhancing cell death in the lungs, thereby expanding our understanding of the molecular mechanism of influenza virus-induced cell death through the interaction with an innate immune receptor.

DOI: https://doi.org/10.1038/s41419-023-05749-5
Front Genet. 2023 ;14 1105673

A single-cell atlas reveals shared and distinct immune responses and metabolic profiles in SARS-CoV-2 and HIV-1 infections.

Tony Pan, Guoshuai Cao, Erting Tang, Yu Zhao, Pablo Penaloza-MacMaster, Yun Fang, Jun Huang.

  Introduction: Within the inflammatory immune response to viral infection, the distribution and cell type-specific profiles of immune cell populations and the immune-mediated viral clearance pathways vary according to the specific virus. Uncovering the immunological similarities and differences between viral infections is critical to understanding disease progression and developing effective vaccines and therapies. Insight into COVID-19 disease progression has been bolstered by the integration of single-cell (sc)RNA-seq data from COVID-19 patients with data from related viruses to compare immune responses. Expanding this concept, we propose that a high-resolution, systematic comparison between immune cells from SARS-CoV-2 infection and an inflammatory infectious disease with a different pathophysiology will provide a more comprehensive picture of the viral clearance pathways that underscore immunological and clinical differences between infections. Methods: Using a novel consensus single-cell annotation method, we integrate previously published scRNA-seq data from 111,566 single PBMCs from 7 COVID-19, 10 HIV-1+, and 3 healthy patients into a unified cellular atlas. We compare in detail the phenotypic features and regulatory pathways in the major immune cell clusters. Results: While immune cells in both COVID-19 and HIV-1+ cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activity, and downregulated mitophagy. Discussion: Our results indicate that differential IFN-I signaling regulates the distinct immune responses in the two diseases, revealing insight into fundamental disease biology and potential therapeutic candidates.

Keywords:  HIV; SARS-CoV-2; Single-cell RNA sequencing; inflammation; metabolic signaling; type 1 interferon

DOI:  https://doi.org/10.3389/fgene.2023.1105673
Virology. 2023 Mar 24. pii: S0042-6822(23)00056-9. [Epub ahead of print]582 12-22

An untargeted metabolomics investigation in liver of flaviviruses-infected mice.

Xiaoyan Zheng, Ran Wang, Chenghong Yin.

  Dengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV) are the three most important flaviviruses, which can cause health problems worldwide. All these flaviviruses can cause liver damage, however, the mechanism of liver injury is still unclear. Metabolomics can give insight into the full complexity of a disease. In our study, we used an LC-MS method to analysis the metabolites in liver samples of the three flaviviruses-infected mice and the non-infected mice. Compared with the control mice, the liver of the DENV-infected, JEV-infected, and ZIKV-infected mice had 32, 34, and 55 differential metabolites. We also found that there were obvious differences in some metabolic pathways among the four groups. Metabonomic analysis of liver is very important for understanding the pathogenesis of flaviviruses.

Keywords:  Flaviviruses; LC–MS; Liver; Metabolomic; Viral mosquito-borne diseases

DOI:  https://doi.org/10.1016/j.virol.2023.03.008