bims-mevinf 2023-05-07 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023‒05‒07
ten papers selected by
Alexander Ivanov

Abnormal glucose metabolism in virus associated sepsis.
Autophagy and unfolded protein response induction: a crosstalk between street rabies virus and the host.
Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.
Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation.
Chikungunya virus infection in Aedes aegypti is modulated by L-cysteine, taurine, hypotaurine and glutathione metabolism.
H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells.
An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.
Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I.
Integrated clinical and metabolomic analysis of dengue infection shows molecular signatures associated with host-pathogen interaction in different phases of the disease.
The role of high cholesterol in SARS-CoV-2 infectivity.

Front Cell Infect Microbiol. 2023 ;13 1120769

Abnormal glucose metabolism in virus associated sepsis.

Peng Zhang, Shangwen Pan, Shiying Yuan, You Shang, Huaqing Shu.

  Sepsis is identified as a potentially lethal organ impairment triggered by an inadequate host reaction to infection (Sepsis-3). Viral sepsis is a potentially deadly organ impairment state caused by the host's inappropriate reaction to a viral infection. However, when a viral infection occurs, the metabolism of the infected cell undergoes a variety of changes that cause the host to respond to the infection. But, until now, little has been known about the challenges faced by cellular metabolic alterations that occur during viral infection and how these changes modulate infection. This study concentrates on the alterations in glucose metabolism during viral sepsis and their impact on viral infection, with a view to exploring new potential therapeutic targets for viral sepsis.

Keywords:  antiviral; glucose metabolism; immune cell; sepsis; virus

DOI:  https://doi.org/10.3389/fcimb.2023.1120769
Cell Stress Chaperones. 2023 May 03.

Autophagy and unfolded protein response induction: a crosstalk between street rabies virus and the host.

Shima Poorghobadi, Kazem Baesi, Safoora Gharibzadeh, Reza Shirzad, Mohammad S Khosravy, Maryam Fazeli, Farzaneh Sheikholeslami.

  The endoplasmic reticulum (ER) response mechanism to cellular stress is mediated by the unfolded protein response/ER-associated degradation (UPR/ERAD) pathway. A viral infection can trigger ER stress and engage some transcription factors, depending on the host cell and virus type, activating or inhibiting autophagy. The relationship between ER response and autophagy in rabies has not been investigated yet. In the present study, the mouse brain was infected with street rabies virus (SRABV). Total RNA was extracted from the brains of animals, and cDNA was synthesized. Next, real-time PCR assay was performed using specific primers. The expression of hypoxanthine-guanine phosphoribosyltransferase (Hprt), CCAAT/enhancer binding protein homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), activating transcription factor 6 (ATF6), and caspase 3 (CASP3) genes was also investigated. Based on the results, SRABV caused significant changes in the mRNA expression of ATF6, CHOP, and ASK1 genes in the brains of infected mice in the control group (group V). Treatment of infected cells with the pIRES-EGFP-Beclin-1 vector and rapamycin caused changes in nearly most of the parameters. However, alterations in CASP3 gene expression were only observed when the vector and the virus were simultaneously injected into the cells. Overall, protection and autophagy against cell death induced by SRABV infection can be achieved by activating the ER stress pathway, followed by a marked increase in the expression of ATF6, CHOP, ASK1, and CASP3 genes.

Keywords:  Autophagy; Host cell; Street rabies virus; Transcription factors; Unfolded protein response

DOI:  https://doi.org/10.1007/s12192-023-01335-y
J Virol. 2023 May 03. e0029223

Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.

Xuyang Guo, Yingtong Feng, Xiaojing Zhao, Shuang Qiao, Zhiqian Ma, Zhiwei Li, Haixue Zheng, Shuqi Xiao.

  Chemokine production by epithelial cells is crucial for neutrophil recruitment to sites of inflammation during viral infection. However, the effect of chemokine on epithelia and how chemokine is involved in coronavirus infection remains to be fully understood. Here, we identified an inducible chemokine interleukin-8 (CXCL8/IL-8), which could promote coronavirus porcine epidemic diarrhea virus (PEDV) infection in African green monkey kidney epithelial cells (Vero) and Lilly Laboratories cell-porcine kidney 1 epithelial cells (LLC-PK1). IL-8 deletion restrained cytosolic calcium (Ca2+), whereas IL-8 stimulation improved cytosolic Ca2+. The consumption of Ca2+ restricted PEDV infection. PEDV internalization and budding were obvious reductions when cytosolic Ca2+ was abolished in the presence of Ca2+ chelators. Further study revealed that the upregulated cytosolic Ca2+ redistributes intracellular Ca2+. Finally, we identified that G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-store-operated Ca2+ (SOC) signaling was crucial for enhancive cytosolic Ca2+ and PEDV infection. To our knowledge, this study is the first to uncover the function of chemokine IL-8 during coronavirus PEDV infection in epithelia. PEDV induces IL-8 expression to elevate cytosolic Ca2+, promoting its infection. Our findings reveal a novel role of IL-8 in PEDV infection and suggest that targeting IL-8 could be a new approach to controlling PEDV infection. IMPORTANCE Coronavirus porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that caused severe economic losses worldwide, and more effort is needed to develop economical and efficient vaccines to control or eliminate this disease. The chemokine interleukin-8 (CXCL8/IL-8) is indispensable for the activation and trafficking of inflammatory mediators and tumor progression and metastasis. This study evaluated the effect of IL-8 on PEDV infection in epithelia. We found that IL-8 expression improved cytosolic Ca2+ in epithelia, facilitating PEDV rapid internalization and egress. G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-SOC signaling was activated by IL-8, releasing the intracellular Ca2+ stores from endoplasmic reticulum (ER). These findings provide a better understanding of the role of IL-8 in PEDV-induced immune responses, which will help develop small-molecule drugs for coronavirus cure.

Keywords:  calcium signaling; infection; interleukin-8; porcine epidemic diarrhea virus; therapy

DOI:  https://doi.org/10.1128/jvi.00292-23
Nat Commun. 2023 May 05. 14(1): 2610

Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation.

Yafeng Li, Jessica S Hook, Qing Ding, Xue Xiao, Stephen S Chung, Marcel Mettlen, Lin Xu, Jessica G Moreland, Michalis Agathocleous.

Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.

DOI: https://doi.org/10.1038/s41467-023-37567-w
PLoS Negl Trop Dis. 2023 05;17(5): e0011280

Chikungunya virus infection in Aedes aegypti is modulated by L-cysteine, taurine, hypotaurine and glutathione metabolism.

Ankit Kumar, Jatin Shrinet, Sujatha Sunil.

BACKGROUND: Blood meal and infections cause redox imbalance and oxidative damage in mosquitoes which triggers the mosquito's system to produce antioxidants in response to increased oxidative stress. Important pathways activated owing to redox imbalance include taurine, hypotaurine and glutathione metabolism. The present study was undertaken to evaluate the role of these pathways during chikungunya virus (CHIKV) infection in Aedes aegypti mosquitoes.METHODOLOGY: Using a dietary L-cysteine supplement system, we upregulated these pathways and evaluated oxidative damage and oxidative stress response upon CHIKV infection using protein carbonylation and GST assays. Further, using a dsRNA based approach, we silenced some of the genes involved in synthesis and transport of taurine and hypotaurine and then evaluated the impact of these genes on CHIKV infection and redox biology in the mosquitoes.
CONCLUSIONS: We report that CHIKV infection exerts oxidative stress in the A. aegypti, leading to oxidative damage and as a response, an elevated GST activity was observed. It was also observed that dietary L-cysteine treatment restricted CHIKV infection in A. aegypti mosquitoes. This L-cysteine mediated CHIKV inhibition was coincided by enhanced GST activity that further resulted in reduced oxidative damage during the infection. We also report that silencing of genes involved in synthesis of taurine and hypotaurine modulates CHIKV infection and redox biology of Aedes mosquitoes during the infection.

DOI: https://doi.org/10.1371/journal.pntd.0011280
Free Radic Biol Med. 2023 May 03. pii: S0891-5849(23)00408-2. [Epub ahead of print]

H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells.

Chengcheng Liu, Xinhao Wu, Xin Bing, Wenwen Qi, Fangyuan Zhu, Na Guo, Chengzhilin Li, Xiaochen Gao, Xue Cao, Miaoqing Zhao, Ming Xia.

  Influenza A virus can induce nasal inflammation by stimulating the death of nasal mucosa epithelium, however, the mechanism is not clear. In this study, to study the causes and mechanisms of nasal mucosa epithelial cell death caused by Influenza A virus H1N1, we isolated and cultured human nasal epithelial progenitor cells (hNEPCs) and exposed them to H1N1 virus after leading differentiation. Then we performed high-resolution untargeted metabolomics and RNAseq analysis of human nasal epithelial cells (hNECs) infected with H1N1 virus. Surprisingly, H1N1 virus infection caused the differential expression of a large number of ferroptosis related genes and metabolites in hNECs. Furthermore, we have observed a significant reduction in Nrf2/KEAP1 expression, GCLC expression, and abnormal glutaminolysis. By constructing overexpression vector of GCLC and the shRNAs of GCLC and Keap1, we determined the role of NRF2-KEAP1-GCLC signaling pathway in H1N1 virus-induced ferroptosis. In addition, A glutaminase antagonist, JHU-083, also demonstrated that glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and ferroptosis. According to this study, H1N1 virus can induce the ferroptosis of hNECs via the NRF2-KEAP1-GCLC signal pathway and glutaminolysis, leading to nasal mucosal epithelial inflammation. This discovery is expected to provide an attractive therapeutic target for viral-induced nasal inflammation.

Keywords:  Ferroptosis; Glutaminolysis; Influenza A virus; Multiomics analysis; NRF2-KEAP1-GCLC; Nasal mucosal epithelial cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.004
PLoS Pathog. 2023 May 03. 19(5): e1011323

An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.

COVIDsortium Investigators

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects. Trial registration: NCT04318314.

DOI: https://doi.org/10.1371/journal.ppat.1011323
PLoS Pathog. 2023 May 01. 19(5): e1011371

Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I.

Huizi Li, Cunhao Lin, Wenbao Qi, ZhenZhen Sun, Zhenxin Xie, Weixin Jia, Zhangyong Ning.

Senecavirus A (SVA)-induced porcine idiopathic vesicular disease has caused huge economic losses worldwide. Glucose metabolism in the host cell is essential for SVA proliferation; however, the impact of the virus on glucose metabolism in host cells and the subsequent effects are still unknown. Here, glycolysis induced by SVA is shown to facilitate virus replication by promoting lactate production, which then attenuates the interaction between the mitochondrial antiviral-signaling protein (MAVS) and retinoic acid-inducible gene I (RIG-I). SVA induces glycolysis in PK-15 cells, as indicated by significantly increased expression of hexokinase 2 (HK2), 6-phosphofructokinase (PFKM), pyruvate kinase M (PKM), phosphoglycerate kinase 1 (PGK1), hypoxia-inducible factor-1 alpha (HIF-1α), and superoxide dismutase-2 (SOD2) in a dose-and replication-dependent manner, and enhanced lactate production, while reducing ATP generation. Overexpression of PKM, PGK1, HIF-1α, and PDK3 in PK-15 cells and high glucose concentrations promote SVA replication, while glycolytic inhibitors decrease it. Inhibition of RLR signaling allowed better replication of SVA by promoting lactate production to attenuate the interaction between MAVS and RIG-I, and regulatory effect of glycolysis on replication of SVA was mainly via RIG-I signaling. SVA infection in mice increased expression of PKM and PGK1 in tissues and serum yields of lactate. Mice treated with high glucose and administered sodium lactate showed elevated lactate levels and better SVA replication, as well as suppressed induction of RIG-I, interferon beta (IFNβ), IFNα, interferon-stimulated gene 15 (ISG15), and interleukin 6 (IL-6). The inhibitory effect on interferons was lower in mice administered sodium oxamate and low glucose compared to the high glucose, indicating that RLR signaling was inhibited by SVA infection through lactate in vitro and in vivo. These results provide a new perspective on the relationship between metabolism and innate immunity of the host in SVA infection, suggesting that glycolysis or lactate may be new targets against the virus.

DOI: https://doi.org/10.1371/journal.ppat.1011371
Metabolomics. 2023 May 02. 19(5): 47

Integrated clinical and metabolomic analysis of dengue infection shows molecular signatures associated with host-pathogen interaction in different phases of the disease.

Sriram Rathnakumar, Naga Sai Visweswar Kambhampati, R Saiswaroop, Sai Sanwid Pradhan, G Ramkumar, Nirmala Beeraka, Gopi Krishna Muddu, Sandeep Kumar, Sai Kiran Javvaji, Ashish Parangoankar, Venketesh Sivaramakrishnan, Sai Sathish Ramamurthy.

  PURPOSE: Dengue is a mosquito vector-borne disease caused by the dengue virus, which affects 125 million people globally. The disease causes considerable morbidity. The disease, based on symptoms, is classified into three characteristic phases, which can further lead to complications in the second phase. Molecular signatures that are associated with the three phases have not been well characterized. We performed an integrated clinical and metabolomic analysis of our patient cohort and compared it with omics data from the literature to identify signatures unique to the different phases.METHODS: The dengue patients are recruited by clinicians after standard-of-care diagnostic tests and evaluation of symptoms. Blood from the patients was collected. NS1 antigen, IgM, IgG antibodies, and cytokines in serum were analyzed using ELISA. Targeted metabolomics was performed using LC-MS triple quad. The results were compared with analyzed transcriptomic data from the GEO database and metabolomic data sets from the literature.
RESULTS: The dengue patients displayed characteristic features of the disease, including elevated NS1 levels. TNF-α was found to be elevated in all three phases compared to healthy controls. The metabolic pathways were found to be deregulated compared to healthy controls only in phases I and II of dengue patients. The pathways represent viral replication and host response mediated pathways. The major pathways include nucleotide metabolism of various amino acids and fatty acids, biotin, etc. CONCLUSION: The results show elevated TNF-α and metabolites that are characteristic of viral infection and host response. IL10 and IFN-γ were not significant, consistent with the absence of any complications.

Keywords:  Biomarkers; Clinical analysis; Dengue fever; Host-pathogen interaction; Metabolomics; Molecular signatures; Transcriptomics

DOI:  https://doi.org/10.1007/s11306-023-02011-z
J Biol Chem. 2023 Apr 27. pii: S0021-9258(23)01791-X. [Epub ahead of print] 104763

The role of high cholesterol in SARS-CoV-2 infectivity.

Hao Wang, Zixuan Yuan, Mahmud Arif Pavel, Sonia Mediouni Jablonski, Joseph Jablonski, Robert Hobson, Susana Valente, Chakravarthy B Reddy, Scott B Hansen.

Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus binds to angiotensinogen converting enzyme 2 (ACE2) which mediates viral entry into mammalian cells. COVID19 is notably severe in elderly and those with underlying chronic conditions. The cause of selective severity is not well understood. Here we show cholesterol and the signaling lipid phosphatidyl-inositol 4,5 bisphosphate (PIP2) regulate viral infectivity through the localization of ACE2's into nanoscopic (<200 nm) lipid clusters. Uptake of cholesterol into cell membranes (a condition common to chronic disease) causes ACE2 to move from PIP2 lipids to endocytic ganglioside (GM1) lipids, where the virus is optimally located for viral entry. In mice, age, and high fat diet increase lung tissue cholesterol by up to 40%. And in smokers with chronic disease, cholesterol is elevated two-fold, a magnitude of change that dramatically increases infectivity of virus in cell culture. We conclude increasing the ACE2 location near endocytic lipids increases viral infectivity and may help explain the selective severity of COVID-19 in aged and diseased populations.

DOI: https://doi.org/10.1016/j.jbc.2023.104763