scholarly journals Metabolic Reprogramming of Host Cells in Response to Enteroviral Infection

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 473 ◽  
Author(s):  
Mei-Ling Cheng ◽  
Kun-Yi Chien ◽  
Chien-Hsueh Lai ◽  
Guan-Jie Li ◽  
Jui-Fen Lin ◽  
...  
Keyword(s):  
Viral Replication ◽  
Host Cell ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Enterovirus 71 ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Glutamine Supplementation ◽  
Aspartate Transcarbamylase ◽  
Functional Changes

Enterovirus 71 (EV71) infection is an endemic disease in Southeast Asia and China. We have previously shown that EV71 virus causes functional changes in mitochondria. It is speculative whether EV71 virus alters the host cell metabolism to its own benefit. Using a metabolomics approach, we demonstrate that EV71-infected Vero cells had significant changes in metabolism. Glutathione and its related metabolites, and several amino acids, such as glutamate and aspartate, changed significantly with the infectious dose of virus. Other pathways, including glycolysis and tricarboxylic acid cycle, were also altered. A change in glutamine/glutamate metabolism is critical to the viral infection. The presence of glutamine in culture medium was associated with an increase in viral replication. Dimethyl α-ketoglutarate treatment partially mimicked the effect of glutamine supplementation. In addition, the immunoblot analysis revealed that the expression of glutamate dehydrogenase (GDH) and trifunctional carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) increased during infection. Knockdown of expression of glutaminase (GLS), GDH and CAD drastically reduced the cytopathic effect (CPE) and viral replication. Furthermore, we found that CAD bound VP1 to promote the de novo pyrimidine synthesis. Our findings suggest that virus may induce metabolic reprogramming of host cells to promote its replication through interactions between viral and host cell proteins.

scholarly journals Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment

2016 ◽  
Vol 38 (3) ◽  
pp. 392-401 ◽  
Author(s):  
Ting Zhong ◽  
Li-ying Zhang ◽  
Zeng-yan Wang ◽  
Yue Wang ◽  
Feng-mei Song ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Viral Replication ◽  
Host Cell ◽  
Enterovirus 71

scholarly journals Host cell amplification of nutritional stress contributes to persistence in Chlamydia trachomatis

2021 ◽  
Author(s):  
Nick D. Pokorzynski ◽  
REY CARABEO
Keyword(s):  
Chlamydia Trachomatis ◽  
Host Cell ◽  
De Novo ◽  
Host Cells ◽  
Guanine Nucleotide ◽  
Nucleotide Synthesis ◽  
Rate Limiting Step ◽  
Metabolic Consequence ◽  
Rate Limiting ◽  
Insight Into

Persistence, a viable, but non-replicating state has been implicated in diseases caused by Chlamydia trachomatis. Multiple nutritional stressors produce a superficially similar "persistent" state, yet no systematic comparison has been made to determine their likeness. We employed host-pathogen dual RNA-sequencing under both iron- and tryptophan-starved conditions to gain insight into chlamydial persistence and identify contributions by the host cell. Analysis of the transcriptome of iron- or tryptophan-starved Chlamydia revealed a common "core" component and a stress-specific "accessory" subset. Despite the overall transcriptomic differences of host cells starved for either iron or tryptophan, both stressors induced persistence. A common metabolic consequence of the stressors was a reduction in intracellular GTP levels. Mizoribine inhibition of IMDPH1, which catalyzes the rate-limiting step in de novo guanine nucleotide synthesis reproduced to a similar extent GTP depletion, and inhibited chlamydial growth as expected for a pathogen that is auxotrophic for GTP. Thus, the reduction of guanine nucleotide synthesis manifests amplification of either iron or tryptophan starvation contributing to persistence. These findings illustrate that a nutritionally stressed host cell remains effective in arresting growth of Chlamydia by targeting metabolic pathways required by the pathogen.

scholarly journals Developmental changes and metabolic reprogramming during establishment of infection and progression of Trypanosoma brucei brucei through its insect host

2021 ◽  
Vol 15 (9) ◽  
pp. e0009504
Author(s):  
Arunasalam Naguleswaran ◽  
Paula Fernandes ◽  
Shubha Bevkal ◽  
Ruth Rehmann ◽  
Pamela Nicholson ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Surface Proteins ◽  
Metabolic Reprogramming ◽  
Tsetse Flies ◽  
Nucleotide Polymorphisms ◽  
Sequencing Technologies ◽  
A Genome ◽  
Animal Trypanosomiasis

Trypanosoma brucei ssp., unicellular parasites causing human and animal trypanosomiasis, are transmitted between mammals by tsetse flies. Periodic changes in variant surface glycoproteins (VSG), which form the parasite coat in the mammal, allow them to evade the host immune response. Different isolates of T. brucei show heterogeneity in their repertoires of VSG genes and have single nucleotide polymorphisms and indels that can impact on genome editing. T. brucei brucei EATRO1125 (AnTaR1 serodeme) is an isolate that is used increasingly often because it is pleomorphic in mammals and fly transmissible, two characteristics that have been lost by the most commonly used laboratory stocks. We present a genome assembly of EATRO1125, including contigs for the intermediate chromosomes and minichromosomes that serve as repositories of VSG genes. In addition, de novo transcriptome assemblies were performed using Illumina sequences from tsetse-derived trypanosomes. Reads of 150 bases enabled closely related members of multigene families to be discriminated. This revealed that the transcriptome of midgut-derived parasites is dynamic, starting with the expression of high affinity hexose transporters and glycolytic enzymes and then switching to proline uptake and catabolism. These changes resemble the transition from early to late procyclic forms in culture. Further metabolic reprogramming, including upregulation of tricarboxylic acid cycle enzymes, occurs in the proventriculus. Many transcripts upregulated in the salivary glands encode surface proteins, among them 7 metacyclic VSGs, multiple BARPs and GCS1/HAP2, a marker for gametes. A novel family of transmembrane proteins, containing polythreonine stretches that are predicted to be O-glycosylation sites, was also identified. Finally, RNA-Seq data were used to create an optimised annotation file with 5’ and 3’ untranslated regions accurately mapped for 9302 genes. We anticipate that this will be of use in identifying transcripts obtained by single cell sequencing technologies.

scholarly journals Metabolomics Analysis Reveals Deranged Energy Metabolism and Amino Acid Metabolic Reprogramming in Dogs With Myxomatous Mitral Valve Disease

2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Qinghong Li ◽  
Éva Larouche‐Lebel ◽  
Kerry A. Loughran ◽  
Terry P. Huh ◽  
Jan S. Suchodolski ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Metabolism ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Linear Regression Analysis ◽  
Left Ventricular ◽  
Metabolic Reprogramming ◽  
Valve Disease

Background Myxomatous mitral valve disease (MMVD), a naturally occurring heart disease, affects 10% to 15% of the canine population. Canine MMVD shares many similarities with human MMVD. Untargeted metabolomics was performed to identify changes in metabolic pathways and biomarkers with potential clinical utilities. Methods and Results Serum samples from 27 healthy, 22 stage B1, 18 stage B2 preclinical MMVD dogs, and 17 MMVD dogs with a history of congestive heart failure (CHF) were analyzed. Linear regression analysis identified 173 known metabolites whose concentrations were different among the 4 groups (adjusted P <0.05), of which 40% belonged to amino acid super pathways, while 30% were lipids. More than 50% of significant metabolites were correlated with left atrial diameter but not left ventricular dimension. Acylcarnitines, tricarboxylic acid cycle intermediates, and creatine accumulated in proportion to MMVD severity. α‐Ketobutyrate and ketone bodies were increased as MMVD advanced. Nicotinamide, a key substrate of the main nicotinamide adenine dinucleotide (NAD + ) salvage pathway, was decreased, while quinolinate of the de novo NAD + biosynthesis was increased in CHF dogs versus healthy dogs. 3‐Methylhistidine, marker for myofibrillar protein degradation, was higher in CHF dogs than non‐CHF dogs. Trimethylamine N‐oxide (TMAO) and TMAO–producing precursors, including carnitine, phosphatidylcholine, betaine, and trimethyllysine, were increased in CHF dogs versus non‐CHF dogs. Elevated levels of uremic toxins, including guanidino compounds, TMAO, and urea, were observed in CHF dogs. Pathway analysis highlighted the importance of bioenergetics and amino acid metabolism in canine MMVD. Conclusions Our study revealed altered energy metabolism, amino acid metabolic programming, and reduced renal function in the development of MMVD and CHF. Complex interplays along the heart‐kidney‐gut axis were implicated.

scholarly journals Epstein-Barr virus inactivates the transcriptome and disrupts the chromatin architecture of its host cell in the first phase of lytic reactivation

2019 ◽  
Author(s):  
Alexander Buschle ◽  
Paulina Mrozek-Gorska ◽  
Stefan Krebs ◽  
Helmut Blum ◽  
Filippo M. Cernilogar ◽  
...  
Keyword(s):  
Host Cell ◽  
Epstein Barr Virus ◽  
De Novo ◽  
Human Tumor ◽  
Regulatory Elements ◽  
Lytic Cycle ◽  
Host Cells ◽  
Dependent Manner ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV), a herpes virus also termed HHV 4 and the first identified human tumor virus, establishes a stable long-term latent infection in human B cells, its preferred host. Upon induction of EBV’s lytic phase the latently infected cells turn into a virus factory, a process, that is governed by EBV. In the lytic, productive phase all herpesviruses ensure the efficient induction of all lytic viral genes to produce progeny, but certain of these genes also repress the ensuing antiviral responses of the virally infected host cells, regulate their apoptotic death or control the cellular transcriptome. We now find that EBV causes previously unknown massive and global alterations in the chromatin of its host cell upon induction of the viral lytic phase and prior to the onset of viral DNA replication. The viral initiator protein of the lytic cycle, BZLF1, binds to >105binding sites with different sequence motifs in cellular chromatin and in a concentration dependent manner. Concomitant with DNA binding, silent chromatin opens locally as shown by ATAC-seq experiments, while previously wide-open cellular chromatin becomes inaccessible on a global scale within hours. While viral transcripts increase drastically, the induction of the lytic phase results in a massive reduction of cellular transcripts and a loss of chromatin-chromatin interactions of cellular promoters with their distal regulatory elements as shown in Capture-C experiments. Our data document that EBV’s lytic cycle induces discrete early processes that disrupt the architecture of host cellular chromatin and repress the cellular epigenome and transcriptome likely supporting the efficientde novosynthesis of this herpesvirus.

scholarly journals Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Joseph A. Combs ◽  
Elizabeth B. Norton ◽  
Zubaida R. Saifudeen ◽  
Kerstin Honer Zu Bentrup ◽  
Prasad V. Katakam ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Host Cell ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Cell Metabolism ◽  
Acute Infection ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Functional Changes ◽  
Elevated Rate

ABSTRACT Human cytomegalovirus (HCMV) is a large DNA herpesvirus that is highly prevalent in the human population. HCMV can result in severe direct and indirect pathologies under immunosuppressed conditions and is the leading cause of birth defects related to infectious disease. Currently, the effect of HCMV infection on host cell metabolism as an increase in glycolysis during infection has been defined. We have observed that oxidative phosphorylation is also increased. We have identified morphological and functional changes to host mitochondria during HCMV infection. The mitochondrial network undergoes fission events after HCMV infection. Interestingly, the network does not undergo fusion. At the same time, mitochondrial mass and membrane potential increase. The electron transport chain (ETC) functions at an elevated rate, resulting in the release of increased reactive oxygen species. Surprisingly, despite the stress applied to the host mitochondria, the network is capable of responding to and meeting the increased bioenergetic and biosynthetic demands placed on it. When mitochondrial DNA is depleted from the cells, we observed severe impairment of viral replication. Mitochondrial DNA encodes many of the ETC components. These findings suggest that the host cell ETC is essential to HCMV replication. Our studies suggest the host cell mitochondria may be a therapeutic target. IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus present in up to 85% of some populations. Like all herpesviruses, HCMV infection is for life. No vaccine is currently available, neutralizing antibody therapies are ineffective, and current antivirals have limited long-term efficacy due to side effects and potential for viral mutation and resistance. The significance of this research is in understanding how HCMV manipulates the host mitochondria to support bioenergetic and biosynthetic requirements for replication. Despite a large genome, HCMV relies exclusively on host cells for metabolic functions. By understanding the dependency of HCMV on the mitochondria, we could exploit these requirements and develop novel antivirals.

scholarly journals Involvement of Host ATR-CHK1 Pathway in Hepatitis B Virus Covalently Closed Circular DNA Formation

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jun Luo ◽  
Laurie Luckenbaugh ◽  
Hui Hu ◽  
Zhipeng Yan ◽  
Lu Gao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Replication ◽  
Host Cell ◽  
Hbv Infection ◽  
Host Cells ◽  
B Virus ◽  
Cellular Dna ◽  
Dna Processing

ABSTRACT The covalently closed circular (CCC) DNA of hepatitis B virus (HBV) functions as the only viral transcriptional template capable of producing all viral RNA species and is essential to initiate and sustain viral replication. CCC DNA is converted from a relaxed circular (RC) DNA, in which neither of the two DNA strands is covalently closed. As RC DNA mimics damaged cellular DNA, the host cell DNA damage repair (DDR) system is thought to be responsible for HBV CCC DNA formation. The potential role of two major cellular DDR pathways, the ataxia telangiectasia mutated (ATM) pathway and the ATM and Rad3-related (ATR) pathway, in HBV CCC DNA formation was thus investigated. Inhibition, or expression knockdown, of ATR and its downstream signaling factor CHK1, but not of ATM, decreased CCC DNA formation during de novo HBV infection, as well as intracellular CCC DNA amplification, when RC DNA from extracellular virions and intracellular nucleocapsids, respectively, is converted to CCC DNA. Furthermore, a novel RC DNA processing product with 5′ truncated minus strands was detected when the ATR-CHK1 pathway was inhibited, further indicating that this pathway controls RC DNA processing during its conversion to CCC DNA. These results provide new insights into how host cells recognize and process HBV RC DNA in order to produce CCC DNA and have implications for potential means to block CCC DNA production. IMPORTANCE Hepatitis B virus (HBV) chronically infects hundreds of millions of people and remains a major cause of viral hepatitis, cirrhosis, and liver cancer. HBV persistence is sustained by a viral nuclear episome that directs all viral gene expression needed to support viral replication. The episome is converted from an incomplete DNA precursor in viral particles in an ill-understood process. We report here that the incomplete DNA precursor is recognized by the host cell in a way similar to the sensing of damaged cellular DNA for subsequent repair to form the nuclear episome. Intense efforts are ongoing to develop novel antiviral strategies to eliminate CCC DNA so as to cure chronic HBV infection. Our results here provide novel insights into, and suggest novel ways of perturbing, the process of episome formation. Furthermore, our results inform mechanisms of cellular DNA damage recognition and repair, processes essential for normal cell growth.

scholarly journals Morphological, Biochemical, and Functional Study of Viral Replication Compartments Isolated from Adenovirus-Infected Cells

2016 ◽  
Vol 90 (7) ◽  
pp. 3411-3427 ◽  
Author(s):  
Paloma Hidalgo ◽  
Lourdes Anzures ◽  
Armando Hernández-Mendoza ◽  
Adán Guerrero ◽  
Christopher D. Wood ◽  
...  
Keyword(s):  
Viral Replication ◽  
Host Cell ◽  
Viral Genome ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Functional Study ◽  
Viral Dna ◽  
Superresolution Microscopy ◽  
Infected Cells ◽  
Efficient Viral Replication

ABSTRACTAdenovirus (Ad) replication compartments (RC) are nuclear microenvironments where the viral genome is replicated and a coordinated program of late gene expression is established. These virus-induced nuclear sites seem to behave as central hubs for the regulation of virus-host cell interactions, since proteins that promote efficient viral replication as well as factors that participate in the antiviral response are coopted and concentrated there. To gain further insight into the activities of viral RC, here we report, for the first time, the morphology, composition, and activities of RC isolated from Ad-infected cells. Morphological analyses of isolated RC particles by superresolution microscopy showed that they were indistinguishable from RC within infected cells and that they displayed a dynamic compartmentalization. Furthermore, the RC-containing fractions (RCf) proved to be functional, as they directedde novosynthesis of viral DNA and RNA as well as RNA splicing, activities that are associated with RCin vivo. A detailed analysis of the production of viral late mRNA from RCf at different times postinfection revealed that viral mRNA splicing occurs in RC and that the synthesis, posttranscriptional processing, and release from RC to the nucleoplasm of individual viral late transcripts are spatiotemporally separate events. The results presented here demonstrate that RCf are a powerful system for detailed study into RC structure, composition, and activities and, as a result, the determination of the molecular mechanisms that induce the formation of these viral sites of adenoviruses and other nuclear-replicating viruses.IMPORTANCERC may represent molecular hubs where many aspects of virus-host cell interaction are controlled. Here, we show by superresolution microscopy that RCf have morphologies similar to those of RC within Ad-infected cells and that they appear to be compartmentalized, as nucleolin and DBP display different localization in the periphery of these viral sites. RCf proved to be functional, as they directde novosynthesis of viral DNA and mRNA, allowing the detailed study of the regulation of viral genome replication and expression. Furthermore, we show that the synthesis and splicing of individual viral late mRNA occurs in RC and that they are subject to different temporal patterns of regulation, from their synthesis to their splicing and release from RC to the nucleoplasm. Hence, RCf represent a novel system to study molecular mechanisms that are orchestrated in viral RC to take control of the infected cell and promote an efficient viral replication cycle.

scholarly journals Developmental changes and metabolic reprogramming during establishment of infection and progression of Trypanosoma brucei brucei through its insect host

2021 ◽  
Author(s):  
Arunasalam Naguleswaran ◽  
Paula Fernandes ◽  
Shubha Bevkal ◽  
Ruth Rehmann ◽  
Pamela Nicholson ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Surface Proteins ◽  
Metabolic Reprogramming ◽  
Tsetse Flies ◽  
Nucleotide Polymorphisms ◽  
Sequencing Technologies ◽  
A Genome ◽  
Animal Trypanosomiasis

Trypanosoma brucei ssp , unicellular parasites causing human and animal trypanosomiasis, are transmitted between mammals by tsetse flies. Periodic changes in variant surface glycoproteins (VSG), which form the parasite coat in the mammal, allow them to evade the host immune response. Different isolates of  T. brucei  show heterogeneity in their repertoires of VSG genes and have single nucleotide polymorphisms and indels that can impact on genome editing.  T. brucei brucei  EATRO1125 (AnTaR1 serodeme) is an isolate that is used increasingly often because it is pleomorphic in mammals and fly transmissible, two characteristics that have been lost by the most commonly used laboratory stocks.  We present a genome assembly of EATRO1125, including contigs for the intermediate and mini-chromosomes that serve as repositories of VSG genes. In addition,  de novo  transcriptome assemblies were performed using Illumina sequences from tsetse-derived trypanosomes.  Reads of 150 bases enabled closely related members of multigene families to be discriminated. This revealed that the transcriptome of midgut-derived parasites is dynamic, starting with the expression of high affinity hexose transporters and glycolytic enzymes and then switching to proline uptake and catabolism. These changes resemble the transition from early to late procyclic forms in culture. Further metabolic reprogramming, including upregulation of tricarboxylic acid cycle enzymes, occurs in the proventriculus.  Many transcripts upregulated in the salivary glands encode surface proteins, among them 7 metacyclic VSGs, multiple BARPs and GCS1/HAP2, a marker for gametes. A novel family of transmembrane proteins, containing polythreonine stretches that are predicted to be O-glycosylation sites, was also identified.  Finally, RNA-Seq data were used to create an optimised annotation file with 5’ and 3’ untranslated regions accurately mapped for 9302 genes.  We anticipate that this will be of use in identifying transcripts obtained by single cell sequencing technologies.

scholarly journals The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Francisco Javier Sánchez-García ◽  
Celia Angélica Pérez-Hernández ◽  
Miguel Rodríguez-Murillo ◽  
María Maximina Bertha Moreno-Altamirano
Keyword(s):  
Viral Replication ◽  
Viral Infections ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Replication Cycle ◽  
Host Cells ◽  
Productive Infection ◽  
The Tca Cycle

Host cell metabolism is essential for the viral replication cycle and, therefore, for productive infection. Energy (ATP) is required for the receptor-mediated attachment of viral particles to susceptible cells and for their entry into the cytoplasm. Host cells must synthesize an array of biomolecules and engage in intracellular trafficking processes to enable viruses to complete their replication cycle. The tricarboxylic acid (TCA) cycle has a key role in ATP production as well as in the synthesis of the biomolecules needed for viral replication. The final assembly and budding process of enveloped viruses, for instance, require lipids, and the TCA cycle provides the precursor (citrate) for fatty acid synthesis (FAS). Viral infections may induce host inflammation and TCA cycle metabolic intermediates participate in this process, notably citrate and succinate. On the other hand, viral infections may promote the synthesis of itaconate from TCA cis-aconitate. Itaconate harbors anti-inflammatory, anti-oxidant, and anti-microbial properties. Fumarate is another TCA cycle intermediate with immunoregulatory properties, and its derivatives such as dimethyl fumarate (DMF) are therapeutic candidates for the contention of virus-induced hyper-inflammation and oxidative stress. The TCA cycle is at the core of viral infection and replication as well as viral pathogenesis and anti-viral immunity. This review highlights the role of the TCA cycle in viral infections and explores recent advances in the fast-moving field of virometabolism.

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