bims-mevinf 2023-09-24 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–09–24
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Human muscle cells sensitivity to chikungunya virus infection relies on their glycolysis activity and differentiation stage.
Glycolytic metabolite phosphoenolpyruvate protects host from viral infection through promoting AATK expression.
Amino acid metabolism dysregulation associated with inflammation and insulin resistance in HIV-infected individuals with metabolic disorders.
Cell-specific genome-scale metabolic modeling of SARS-CoV-2-infected lung to identify antiviral enzymes.
PKR-mediated stress response enhances dengue and Zika virus replication.
Transcriptomic analysis reveals upregulated host metabolisms and downregulated immune responses or cell death induced by acute African swine fever virus infection.
Mechanisms of Ferritinophagy and Ferroptosis in Diseases.
Viral infections inhibit saponin biosynthesis and photosynthesis in Panax notoginseng.
Cholesterol and Ceramide Facilitate Membrane Fusion Mediated by the Fusion Peptide of the SARS-CoV-2 Spike Protein.

Biochimie. 2023 Sep 14. pii: S0300-9084(23)00214-6. [Epub ahead of print]

Human muscle cells sensitivity to chikungunya virus infection relies on their glycolysis activity and differentiation stage.

M Jaquet, M Bengue, K Lambert, G Carnac, D Missé, C Bisbal.

  Changes to our environment have led to the emergence of human pathogens such as chikungunya virus. Chikungunya virus infection is today a major public health concern. It is a debilitating chronic disease impeding patients' mobility, affecting millions of people. Disease development relies on skeletal muscle infection. The importance of skeletal muscle in chikungunya virus infection led to the hypothesis that it could serve as a viral reservoir and could participate to virus persistence. Here we questioned the interconnection between skeletal muscle cells metabolism, their differentiation stage and the infectivity of the chikungunya virus. We infected human skeletal muscle stem cells at different stages of differentiation with chikungunya virus to study the impact of their metabolism on virus production and inversely the impact of virus on cell metabolism. We observed that chikungunya virus infectivity is cell differentiation and metabolism-dependent. Chikungunya virus interferes with the cellular metabolism in quiescent undifferentiated and proliferative muscle cells. Moreover, activation of chikungunya infected quiescent muscle stem cells, induces their proliferation, increases glycolysis and amplifies virus production. Therefore, our results showed that Chikungunya virus infectivity and the antiviral response of skeletal muscle cells relies on their energetic metabolism and their differentiation stage. Then, muscle stem cells could serve as viral reservoir producing virus after their activation.

Keywords:  Chikungunya virus; Human skeletal muscle; Metabolism; Stem cells; Viral infection; Viral reservoir

DOI:  https://doi.org/10.1016/j.biochi.2023.09.005
Eur J Immunol. 2023 Sep 19. e2350536

Glycolytic metabolite phosphoenolpyruvate protects host from viral infection through promoting AATK expression.

Lu Zhao, Renjie Song, Yang Liu.

  Viral infections can result in metabolism rewiring of host cells, which in turn affects the viral lifecycle. Phosphoenolpyruvate (PEP), a metabolic intermediate in the glycolytic pathway, plays important roles in several biological processes including anti-tumor T cell immunity. However, whether PEP might participate in modulating viral infection remains largely unknown. Here, we demonstrate that PEP generally inhibits viral replication via upregulation of AATK expression. Targeted metabolomic analyses shown that intracellular level of PEP was increased upon viral infection. PEP treatment significantly restricted viral infection and hence declined subsequent inflammatory response both in vitro and in vivo. Besides, PEP took inhibitory effect on the stage of viral replication and also decreased the mortality of mice with viral infection. Mechanistically, PEP significantly promoted the expression of apoptosis-associated tyrosine kinase (AATK). Knockdown of AATK led to enhanced viral replication and consequent increased levels of cytokines. Moreover, AATK deficiency disabled the antiviral effect of PEP. Together, our study reveals a previously unknown role of PEP in broadly inhibiting viral replication by promoting AATK expression, highlighting the potential application of activation or upregulation of PEP-AATK axis in controlling viral infections. This article is protected by copyright. All rights reserved.

Keywords:  viral infection ⋅ phosphoenolpyruvate ⋅ AATK ⋅ cellular metabolism ⋅ inflammation

DOI:  https://doi.org/10.1002/eji.202350536
Amino Acids. 2023 Sep 19.

Amino acid metabolism dysregulation associated with inflammation and insulin resistance in HIV-infected individuals with metabolic disorders.

Jing Zhang, Yanfang Chen, Mingli Wang, Liuting Zhong, Linghua Li, Zhongwen Yuan, Shangrong Zou.

  Amino acid metabolic profile, particularly its association with clinical characteristics, remains unclear in patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) combined with metabolic disorders. In this study, we performed targeted metabolomic analyses on 64 patients with HIV/AIDS and 21 healthy controls. Twenty-four amino acids and selected intermediate metabolites in the serum were quantitatively detected using high-performance liquid chromatography-tandem mass spectrometry, and characteristic changes and metabolic pathways were analyzed in HIV-infected patients with different degrees of abnormal glucose and lipid metabolism. Spearman's partial correlation was used to analyze the association between amino acids, biochemical parameters, and inflammatory cytokines. The results showed that the main metabolic pathways of the eighteen differential metabolites involved were arginine biosynthesis and metabolism, methionine cycle, and tryptophan metabolism. Fourteen differential amino acid metabolites were positively correlated with nine inflammatory cytokines, including TNF-α, C-reactive protein, IL-1β, and galectin-3 (FDR < 0.1). Kynurenine, ornithine, and homocysteine were positively correlated with fasting blood glucose and insulin resistance index (FDR < 0.1). Our study revealed a multi-pathway imbalance in amino acid metabolism in patients with HIV/AIDS, which was significantly correlated with inflammation and insulin resistance.

Keywords:  Amino acids; Glucose and lipid metabolism; HIV; Inflammation; Insulin resistance; Targeted metabolomics

DOI:  https://doi.org/10.1007/s00726-023-03325-x
FEBS Open Bio. 2023 Sep 21.

Cell-specific genome-scale metabolic modeling of SARS-CoV-2-infected lung to identify antiviral enzymes.

Ke-Lin Chen, Feng-Sheng Wang.

  Computational systems biology plays a key role in the discovery of suitable antiviral targets. We designed a cell-specific, constraint-based modeling technique for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs. We used the gene sequence of the alpha variant of SARS-CoV-2 to build a viral biomass reaction. We also used the mass proportion of lipids between the viral biomass and its host cell to estimate the stoichiometric coefficients of viral lipids in the reaction. We then integrated the viral biomass reaction, the gene expression of the alpha variant of SARS-CoV-2, and the generic human metabolic network Recon3D to reconstruct a cell-specific genome-scale metabolic model. An antiviral target discovery (AVTD) platform was introduced using this model to identify therapeutic drug targets for combating COVID-19. The AVTD platform not only identified antiviral genes for eliminating viral replication but also predicted side effects of treatments. Our computational results revealed that knocking out dihydroorotate dehydrogenase (DHODH) might reduce the synthesis rate of cytidine-5'-triphosphate and uridine-5'-triphosphate, which terminate the viral building blocks of DNA and RNA for SARS-CoV-2 replication. Our results also indicated that DHODH is a promising antiviral target that causes minor side effects, which is consistent with the results of recent reports. Moreover, we discovered that the genes that participate in the de novo biosynthesis of glycerophospholipids and ceramides become unidentifiable if the viral biomass reaction does not involve the stoichiometry of lipids.

Keywords:  Fuzzy optimization; antiviral target design; constraint-based model; genome-scale metabolic model; hybrid differential evolution; multilevel optimization

DOI:  https://doi.org/10.1002/2211-5463.13710
mBio. 2023 Sep 21. e0093423

PKR-mediated stress response enhances dengue and Zika virus replication.

Taissa Ricciardi-Jorge, Edroaldo Lummertz da Rocha, Edgar Gonzalez-Kozlova, Gabriela Flavia Rodrigues-Luiz, Brian J Ferguson, Trevor Sweeney, Nerea Irigoyen, Daniel Santos Mansur.

  The mechanisms by which flaviviruses use non-canonical translation to support their replication in host cells are largely unknown. Here, we investigated how the integrated stress response (ISR), which promotes translational arrest by eIF2ɑ phosphorylation (p-eIF2ɑ), regulates flavivirus replication. During dengue virus (DENV) and Zika virus (ZIKV) infection, eIF2ɑ phosphorylation peaked at 24 hours post-infection and was dependent on protein kinase RNA-activated (PKR) but not type I interferon. The ISR is activated downstream of p-eIF2α during infection with either virus, but translation arrest only occurred following DENV4 infection. Despite this difference, both DENV4 and ZIKV replications were impaired in cells lacking PKR, independent of type I interferon/NF-kB signaling or cell viability. By using a ZIKV 5'-untranslated region (UTR) reporter system as a model, we found that this region of the genome is sufficient to promote an enhancement of viral mRNA translation in the presence of an active ISR. Together, we provide evidence that flaviviruses escape ISR translational arrest and co-opt this response to increase viral replication. IMPORTANCE One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5'-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.

Keywords:  PKR; Zika virus; dengue virus; innate immunity; protein translation

DOI:  https://doi.org/10.1128/mbio.00934-23
Front Vet Sci. 2023 ;10 1239926

Transcriptomic analysis reveals upregulated host metabolisms and downregulated immune responses or cell death induced by acute African swine fever virus infection.

Shinuo Cao, Peng Jia, Zhi Wu, Huipeng Lu, Yuting Cheng, Changchun Chen, Mo Zhou, Shanyuan Zhu.

  The African swine fever virus is a virulent and communicable viral disease that can be transmitted by infected swine, contaminated pork products, or soft tick vectors. Nonstructural proteins encoded by ASFV regulate viral replication, transcription, and evasion. However, the mechanisms underlying the host response to ASFV infection remain incompletely understood. In order to enhance comprehension of the biology and molecular mechanisms at distinct time intervals (6, 12, 24 h) post infection, transcriptome analyses were executed to discern differentially expressed genes (DEGs) between ASFV and mock-infected PAMs. The transcriptomic analysis unveiled a total of 1,677, 2,122, and 2,945 upregulated DEGs and 933, 1,148, and 1,422 downregulated DEGs in ASFV- and mock-infected groups at 6, 12, and 24 h.p.i.. The results of the transcriptomic analysis demonstrated that the infection of ASFV significantly stimulated host metabolism pathways while concurrently inhibiting the expression of various immune responses and cell death pathways. Our study offers crucial mechanistic insights into the comprehension of ASFV viral pathogenesis and the multifaceted host immune responses. The genes that were dysregulated may serve as potential candidates for further exploration of anti-ASFV strategies.

Keywords:  African swine fever virus; cell death; innate immune response; metabolism; transcriptome

DOI:  https://doi.org/10.3389/fvets.2023.1239926
Mol Neurobiol. 2023 Sep 22.

Mechanisms of Ferritinophagy and Ferroptosis in Diseases.

Siqi Li, Ping Huang, Feifan Lai, Ting Zhang, Jiaqi Guan, Haitong Wan, Yu He.

  The discovery of the role of autophagy, particularly the selective form like ferritinophagy, in promoting cells to undergo ferroptosis has inspired us to investigate functional connections between diseases and cell death. Ferroptosis is a novel model of procedural cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS), mitochondrial dysfunction, and neuroinflammatory response. Based on ferroptosis, the study of ferritinophagy is particularly important. In recent years, extensive research has elucidated the role of ferroptosis and ferritinophagy in neurological diseases and anemia, suggesting their potential as therapeutic targets. Besides, the global emergence and rapid transmission of COVID-19, which is caused by SARS-CoV-2, represents a considerable risk to public health worldwide. The potential involvement of ferroptosis in the pathophysiology of brain injury associated with COVID-19 is still unclear. This review summarizes the pathophysiological changes of ferroptosis and ferritinophagy in neurological diseases, anemia, and COVID-19, and hypothesizes that ferritinophagy may be a potential mechanism of ferroptosis. Advancements in these fields will enhance our comprehension of methods to prevent and address neurological disorders, anemia, and COVID-19.

Keywords:  Anemia; COIVD-19; Central nervous system diseases; Ferritinophagy; Ferroptosis; Lipid peroxidation

DOI:  https://doi.org/10.1007/s12035-023-03640-0
Plant Physiol Biochem. 2023 Sep 13. pii: S0981-9428(23)00549-1. [Epub ahead of print]203 108038

Viral infections inhibit saponin biosynthesis and photosynthesis in Panax notoginseng.

Hongjun Chen, Wenyun Li, Xiaohua Chen, Guanze Liu, Xuyan Liu, Xiuming Cui, Diqiu Liu.

  Virus-infected Panax notoginseng plants with chlorotic, mosaic, and pitted leaves are ubiquitous in the primary P. notoginseng-producing region in Wenshan autonomous prefecture, Yunnan province, China. However, the viruses that infect P. notoginseng and the effects of viral infections on the biosynthesis of secondary metabolites and photosynthesis remain unknown. This study identified a variety of viruses infecting P. notoginseng plants via deep-sequencing of small RNA (sRNA). Of the 10 identified viruses, seven had not previously been detected in P. notoginseng, including Cauliflower mosaic virus and Soybean chlorotic mottle virus. In addition, the simultaneous infection of P. notoginseng by Panax notoginseng virus A (PnVA), Panax cryptic virus 4 (PCV4), and Tomato yellow leaf curl China virus (TYLCCNV) was confirmed by PCR. Moreover, a quantitative PCR analysis showed that the expression levels of key genes related to saponin biosynthesis were generally down-regulated in the virus-infected P. notoginseng. Additionally, high-performance liquid chromatography results indicated the saponin content decreased in the roots of virus-infected P. notoginseng plants. The activities of photosynthesis-related enzymes, including ribulose-1,5-bisphosphate carboxylase/oxygenase, fructose 1,6-bisphosphatase, and fructose 1,6-biphosphate aldolase, decreased significantly in the virus-infected P. notoginseng plants. The viral infections also induced the expression of antioxidant genes and increased antioxidant enzyme activities. Furthermore, the expression levels of many resistance-related genes were up-regulated in P. notoginseng plants inoculated with a viral suspension. The study results provide the foundation for future research on P. notoginseng viral diseases, which may lead to the development of enhanced disease control measures.

Keywords:  Antioxidant enzyme; Panax notoginseng; Photosynthesis; Saponin biosynthesis; Small RNA sequencing; Virus disease

DOI:  https://doi.org/10.1016/j.plaphy.2023.108038
ACS Omega. 2023 Sep 12. 8(36): 32729-32739

Cholesterol and Ceramide Facilitate Membrane Fusion Mediated by the Fusion Peptide of the SARS-CoV-2 Spike Protein.

Kristina Niort, Julia Dancourt, Erwan Boedec, Zahra Al Amir Dache, Grégory Lavieu, David Tareste.

SARS-CoV-2 entry into host cells is mediated by the Spike (S) protein of the viral envelope. The S protein is composed of two subunits: S1 that induces binding to the host cell via its interaction with the ACE2 receptor of the cell surface and S2 that triggers fusion between viral and cellular membranes. Fusion by S2 depends on its heptad repeat domains that bring membranes close together and its fusion peptide (FP) that interacts with and perturbs the membrane structure to trigger fusion. Recent studies have suggested that cholesterol and ceramide lipids from the cell surface may facilitate SARS-CoV-2 entry into host cells, but their exact mode of action remains unknown. We have used a combination of in vitro liposome-liposome and in situ cell-cell fusion assays to study the lipid determinants of S-mediated membrane fusion. Our findings reveal that both cholesterol and ceramide lipids facilitate fusion, suggesting that targeting these lipids could be effective against SARS-CoV-2. As a proof of concept, we examined the effect of chlorpromazine (CPZ), an antipsychotic drug known to perturb membrane structure. Our results show that CPZ effectively inhibits S-mediated membrane fusion, thereby potentially impeding SARS-CoV-2 entry into the host cell.

DOI: https://doi.org/10.1021/acsomega.3c03610