bims-rebvin 2023-03-05 papers

bims-rebvin

Biomed News

on Redox biology and metabolism in viral infections

Issue of 2023–03–05
fiveteen papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies.
Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response.
Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies.
Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.
Metabolic regulation of NK cell antiviral functions during cytomegalovirus infection.
Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.
Stress Granules Inhibit Coxsackievirus B3-Mediated Cell Death via Reduction of Mitochondrial Reactive Oxygen Species and Viral Extracellular Release.
Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication.
Retroviral Infection and Commensal Bacteria Dependently Alter the Metabolomic Profile in a Sterile Organ.
Mitochondria Dysfunction at the Heart of Viral Myocarditis: Mechanistic Insights and Therapeutic Implications.
Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.
Overexpression of TRIM16 Reduces the Titer of H5N1 Highly Pathogenic Avian Influenza Virus and Promotes the Expression of Antioxidant Genes through Regulating the SQSTM1-NRF2-KEAP1 Axis.
Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress.
Pinosrtobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism.
Oncolytic Avian Reovirus σA-Modulated Upregulation of the HIF-1α/C-myc/glut1 Pathway to Produce More Energy in Different Cancer Cell Lines Benefiting Virus Replication.

Viruses. 2023 Feb 16. pii: 547. [Epub ahead of print]15(2):

Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies.

Azzam Hamad, Gaukhar M Yusubalieva, Vladimir P Baklaushev, Peter M Chumakov, Anastasiya V Lipatova.

  Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase the long-term survival of glioblastoma patients. Oncolytic viruses (OVs) may be an effective alternative approach. Combining OVs with some modern treatment options may also provide significant benefits for glioblastoma patients. Here we review virotherapy for glioblastomas and describe several OVs and their combination with other therapies. The personalized use of OVs and their combination with other treatment options would become a significant area of research aiming to develop the most effective treatment regimens for glioblastomas.

Keywords:  CAR T; cancer immunotherapy; glioblastoma; immunotherapy; nanoparticles; oncolytic viruses; poliovirus; proteomics; recombinant strain; viral vector

DOI:  https://doi.org/10.3390/v15020547
Viruses. 2023 Feb 07. pii: 464. [Epub ahead of print]15(2):

Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response.

Khursheed Ul Islam, Saleem Anwar, Ayyub A Patel, Mohammed Tarek Mirdad, Mahmoud Tarek Mirdad, Md Iqbal Azmi, Tanveer Ahmad, Zeeshan Fatima, Jawed Iqbal.

  Hepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.

Keywords:  antiviral response; fatty acids; glycerolipids; glycerophospholipids; hepatitis C virus; lipidome

DOI:  https://doi.org/10.3390/v15020464
Viruses. 2023 Feb 13. pii: 525. [Epub ahead of print]15(2):

Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies.

Larissa Menezes Dos Reis, Marcelo Rodrigues Berçot, Bianca Gazieri Castelucci, Ana Julia Estumano Martins, Gisele Castro, Pedro M Moraes-Vieira.

  RNA viruses are known to induce a wide variety of respiratory tract illnesses, from simple colds to the latest coronavirus pandemic, causing effects on public health and the economy worldwide. Influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (MPV), respiratory syncytial virus (RSV), rhinovirus (RhV), and coronavirus (CoV) are some of the most notable RNA viruses. Despite efforts, due to the high mutation rate, there are still no effective and scalable treatments that accompany the rapid emergence of new diseases associated with respiratory RNA viruses. Host-directed therapies have been applied to combat RNA virus infections by interfering with host cell factors that enhance the ability of immune cells to respond against those pathogens. The reprogramming of immune cell metabolism has recently emerged as a central mechanism in orchestrated immunity against respiratory viruses. Therefore, understanding the metabolic signature of immune cells during virus infection may be a promising tool for developing host-directed therapies. In this review, we revisit recent findings on the immunometabolic modulation in response to infection and discuss how these metabolic pathways may be used as targets for new therapies to combat illnesses caused by respiratory RNA viruses.

Keywords:  RNA viruses; host-directed therapies; immune responses; immunometabolism; inflammation; respiratory viruses

DOI:  https://doi.org/10.3390/v15020525
Viruses. 2023 Jan 28. pii: 369. [Epub ahead of print]15(2):

Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.

Miguel Angel Pelaez, María Florencia Torti, Aaron Ezequiel Alvarez De Lauro, Agostina Belén Marquez, Federico Giovannoni, Elsa Beatriz Damonte, Cybele Carina García.

  Junín virus (JUNV), a member of the family Arenaviridae, is the etiological agent of the Argentine hemorrhagic fever, an endemic disease in the rural region of Argentina lacking a specific chemotherapy. Aryl hydrocarbon receptor (AHR) is expressed in several mammalian tissues and has been indicated as a sensor of ligands from variable sources and a modulator of the cell immune response. Interestingly, recent studies have suggested that the activation or depression of the AHR signaling pathway may play a role in the outcome of diverse human viral infections. In the present report, the effect of the pharmacological modulation of AHR on JUNV in vitro infection was analyzed. An initial microarray screening showed that the AHR pathway was overexpressed in JUNV-infected hepatic cells. Concomitantly, the infection of Vero and Huh-7 cells with the JUNV strains IV4454 and Candid#1 was significantly inhibited in a dose-dependent manner by treatment with CH223191, a specific AHR antagonist, as detected by infectivity assays, real-time RT-PCR and immunofluorescence detection of viral proteins. Furthermore, the pro-viral role of AHR in JUNV infection appears to be independent of the IFN-I pathway. Our findings support the promising perspectives of the pharmacological modulation of AHR as a potential target for the control of AHF.

Keywords:  Argentine hemorrhagic fever; Junín virus; arenavirus; aryl hydrocarbon receptor; host therapeutic target

DOI:  https://doi.org/10.3390/v15020369
J Leukoc Biol. 2023 Feb 27. pii: qiad018. [Epub ahead of print]

Metabolic regulation of NK cell antiviral functions during cytomegalovirus infection.

Maria Cimpean, Megan A Cooper.

  Natural killer (NK) cells quickly mount cytotoxic responses, produce cytokines, and proliferate in response to infected or transformed cells. Moreover, they can develop memory, with enhanced effector responses following activation, in some cases with antigen-specificity. To optimally execute these functions, NK cells undergo metabolic reprogramming. Here, we discuss the interplay between metabolism and NK cell function in the context of viral infections. We review findings supporting metabolic regulation of NK cell effector functions, with a focus on NK cell antiviral infection in the context of cytomegalovirus in the mouse (MCMV) and human (HCMV).

Keywords:  cytokines; cytomegalovirus infection; cytotoxicity; interferon gamma; memory; metabolism; natural killer cells; proliferation

DOI:  https://doi.org/10.1093/jleuko/qiad018
Int J Biol Macromol. 2023 Feb 25. pii: S0141-8130(23)00728-6. [Epub ahead of print]235 123834

Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.

Ying-Xue Liu, Jia-Yue Yang, Jun-Long Sun, An-Cheng Wang, Xing-Ya Wang, Lin-Bao Zhu, Hui-Hua Cao, Zhi-Hao Huang, Shi-Huo Liu, Jia-Ping Xu.

  c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.

Keywords:  BmNPV; Bombyx mori; Ferritin heavy-chain homolog; JNK phosphorylation; ROS

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123834
J Microbiol Biotechnol. 2023 Jan 11. 33(5): 1-9

Stress Granules Inhibit Coxsackievirus B3-Mediated Cell Death via Reduction of Mitochondrial Reactive Oxygen Species and Viral Extracellular Release.

Ji-Ye Park, Ok Sarah Shin.

  Stress granules (SGs) are cytoplasmic aggregates of RNA-protein complexes that form in response to various cellular stresses and are known to restrict viral access to host translational machinery. However, the underlying molecular mechanisms of SGs during viral infections require further exploration. In this study, we evaluated the effect of SG formation on cellular responses to coxsackievirus B3 (CVB3) infection. Sodium arsenite (AS)-mediated SG formation suppressed cell death induced by tumor necrosis factor-alpha (TNF-a)/cycloheximide (CHX) treatment in HeLa cells, during which G3BP1, an essential SG component, contributed to the modulation of apoptosis pathways. SG formation in response to AS treatment blocked CVB3-mediated cell death, possibly via the reduction of mitochondrial reactive oxygen species. Furthermore, we examined whether AS treatment would affect small extracellular vesicle (sEV) formation and secretion during CVB3 infection and modulate human monocytic cell (THP-1) response. CVB3-enriched sEVs isolated from HeLa cells were able to infect and replicate THP-1 cells without causing cytotoxicity. Interestingly, sEVs from AS-treated HeLa cells inhibited CVB3 replication in THP-1 cells. These findings suggest that SG formation during CVB3 infection modulates cellular response by inhibiting the release of CVB3-enriched sEVs.

Keywords:  CVB3; G3BP1; apoptosis; mitochondrial reactive oxygen species; small extracellular vesicles; stress granules

DOI:  https://doi.org/10.4014/jmb.2210.10027
Viruses. 2023 Feb 07. pii: 466. [Epub ahead of print]15(2):

Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication.

Barkha Ramnani, Shelby Powell, Adarsh G Shetty, Praveen Manivannan, Brian R Hibbard, Douglas W Leaman, Krishnamurthy Malathi.

  Virus infection activates integrated stress response (ISR) and stress granule (SG) formation and viruses counteract by interfering with SG assembly, suggesting an important role in antiviral defense. The infection of fish cells by Viral Hemorrhagic Septicemia Virus (VHSV), activates the innate immune recognition pathway and the production of type I interferon (IFN). However, the mechanisms by which VHSV interacts with ISR pathway regulating SG formation is poorly understood. Here, we demonstrate that fish cells respond to heat shock, oxidative stress and VHSV infection by forming SG that localized key SG marker, Ras GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1). We show that PKR-like endoplasmic reticulum kinase (PERK), but not (dsRNA)-dependent protein kinase (PKR), is required for VHSV-induced SG formation. Furthermore, in VHSV Ia infected cells, PERK activity is required for IFN production, antiviral signaling and viral replication. SG formation required active virus replication as individual VHSV Ia proteins or inactive virus did not induce SG. Cells lacking G3BP1 produced increased IFN, antiviral genes and viral mRNA, however viral protein synthesis and viral titers were reduced. We show a critical role of the activation of ISR pathway and SG formation highlighting a novel role of G3BP1 in regulating VHSV protein translation and replication.

Keywords:  G3BP1; PERK; VHSV; eIF2α phosphorylation; interferon; stress granule; translation

DOI:  https://doi.org/10.3390/v15020466
Viruses. 2023 Jan 29. pii: 386. [Epub ahead of print]15(2):

Retroviral Infection and Commensal Bacteria Dependently Alter the Metabolomic Profile in a Sterile Organ.

Jessica Spring, Vera Beilinson, Brian C DeFelice, Juan M Sanchez, Michael Fischbach, Alexander Chervonsky, Tatyana Golovkina.

  Both viruses and bacteria produce "pathogen associated molecular patterns" that may affect microbial pathogenesis and anti-microbial responses. Additionally, bacteria produce metabolites, while viruses could change the metabolic profiles of the infected cells. Here, we used an unbiased metabolomics approach to profile metabolites in spleens and blood of murine leukemia virus-infected mice monocolonized with Lactobacillus murinus to show that viral infection significantly changes the metabolite profile of monocolonized mice. We hypothesize that these changes could contribute to viral pathogenesis or to the host response against the virus and thus open a new avenue for future investigations.

Keywords:  commensal bacteria; metabolites; microbiota; retroviruses

DOI:  https://doi.org/10.3390/v15020386
Viruses. 2023 Jan 26. pii: 351. [Epub ahead of print]15(2):

Mitochondria Dysfunction at the Heart of Viral Myocarditis: Mechanistic Insights and Therapeutic Implications.

Yasir Mohamud, Boaz Li, Amirhossein Bahreyni, Honglin Luo.

  The myocardium/heart is the most mitochondria-rich tissue in the human body with mitochondria comprising approximately 30% of total cardiomyocyte volume. As the resident "powerhouse" of cells, mitochondria help to fuel the high energy demands of a continuously beating myocardium. It is no surprise that mitochondrial dysfunction underscores the pathogenesis of many cardiovascular ailments, including those of viral origin such as virus-induced myocarditis. Enteroviruses have been especially linked to injuries of the myocardium and its sequelae dilated cardiomyopathy for which no effective therapies currently exist. Intriguingly, recent mechanistic insights have demonstrated viral infections to directly damage mitochondria, impair the mitochondrial quality control processes of the cell, such as disrupting mitochondrial antiviral innate immune signaling, and promoting mitochondrial-dependent pathological inflammation of the infected myocardium. In this review, we briefly highlight recent insights on the virus-mitochondria crosstalk and discuss the therapeutic implications of targeting mitochondria to preserve heart function and ultimately combat viral myocarditis.

Keywords:  apoptosis; autophagy; enterovirus; innate immune response; mitochondria; mitophagy; myocarditis

DOI:  https://doi.org/10.3390/v15020351
Neurochem Res. 2023 Mar 01.

Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.

Gajendra Singh, Alok Kumar.

  Mitochondria dysfunction may be an important contributor to Japanese encephalitis (JE) viral infection disease pathogenesis. In the current study, we define whether changes in mitochondrial DNA copy number (which is the biomarker for mitochondrial function) and alteration in mitochondria dynamics (fusion and fission) contribute to the pathology of the JE virus in vivo mice model. We found decreased mitochondria copy number, reduced activation of mitochondrial fission (FIS1/DRP1), and increased activation of mitochondrial fusion (MFN1/MFN2/OPA1) genes that are associated with increased NOX2-mediated ROS generation and neuronal cell death following JE virus infection. Furthermore, we found that antioxidant glutathione level decreases. In summary, the following study demonstrates that JE viral infection causes an imbalance in mitochondrial fission/fusion gene activation and promotes NOX2-mediated oxidative stress and cell death, suggesting that intervention in mitochondrial dynamics might be a potential therapeutic strategy for combating oxidative stress and inflammatory process in JE viral infection.

Keywords:  JE viral infection; Mitochondria copy number; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion

DOI:  https://doi.org/10.1007/s11064-023-03898-9
Viruses. 2023 Jan 30. pii: 391. [Epub ahead of print]15(2):

Overexpression of TRIM16 Reduces the Titer of H5N1 Highly Pathogenic Avian Influenza Virus and Promotes the Expression of Antioxidant Genes through Regulating the SQSTM1-NRF2-KEAP1 Axis.

Yanwei Liu, Yifan Wei, Ziwei Zhou, Yongxia Gu, Zifeng Pang, Ming Liao, Hailiang Sun.

  Oxidative stress plays a vital role in viral replication. Tripartite motif containing 16 (TRIM16) is involved in diverse cellular processes. However, the role of TRIM16 in oxidative stress induced by infection of the highly pathogenic H5N1 avian influenza virus (HPAIV) is unclear. We found that under conditions of H5N1 HPAIV infection, reactive oxygen species (ROS) levels in A549 cells peaked at 24 h post infection (hpi), and antioxidant genes' expression levels were down-regulated. Overexpression of TRIM16 in A549 cells resulted in a decrease in the titter of H5N1 HPAIV and led to significant up-regulation of the antioxidant genes' expression levels, which indicates that TRIM16 positively regulates the sequestosome 1/Kelch-like associated enoyl-CoA hydratase 1 protein/nuclear factor erythrocyte 2-derived 2-like 2 (SQSTM1/NRF2/KEAP1) pathway. Under basal conditions, TRIM16 led to a modification of NRF2 through an increase in K63-linked poly-ubiquitination of NRF2. Collectively, our findings provide new insight into understanding TRIM16's role in anti-oxidative stress in H5N1 HPAIV infected A549 cells.

Keywords:  AIV; NRF2; TRIM16; oxidative stress; ubiquitination

DOI:  https://doi.org/10.3390/v15020391
Vaccines (Basel). 2023 Jan 19. pii: 218. [Epub ahead of print]11(2):

Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress.

Celia María Curieses Andrés, José Manuel Pérez de la Lastra, Celia Andrés Juan, Francisco J Plou, Eduardo Pérez-Lebeña.

  Myeloid-derived suppressor cells MDSCs are a heterogeneous population of cells that expand beyond their physiological regulation during pathologies such as cancer, inflammation, bacterial, and viral infections. Their key feature is their remarkable ability to suppress T cell and natural killer NK cell responses. Certain risk factors for severe COVID-19 disease, such as obesity and diabetes, are associated with oxidative stress. The resulting inflammation and oxidative stress can negatively impact the host. Similarly, cancer cells exhibit a sustained increase in intrinsic ROS generation that maintains the oncogenic phenotype and drives tumor progression. By disrupting endoplasmic reticulum calcium channels, intracellular ROS accumulation can disrupt protein folding and ultimately lead to proteostasis failure. In cancer and COVID-19, MDSCs consist of the same two subtypes (PMN-MSDC and M-MDSC). While the main role of polymorphonuclear MDSCs is to dampen the response of T cells and NK killer cells, they also produce reactive oxygen species ROS and reactive nitrogen species RNS. We here review the origin of MDSCs, their expansion mechanisms, and their suppressive functions in the context of cancer and COVID-19 associated with the presence of superoxide anion •O2- and reactive oxygen species ROS.

Keywords:  COVID-19; RNS and RHS; ROS; antimicrobial; cancer; innate immunity; myeloid-derived suppressor cells; reactive species

DOI:  https://doi.org/10.3390/vaccines11020218
Antiviral Res. 2023 Feb 28. pii: S0166-3542(23)00048-7. [Epub ahead of print] 105570

Pinosrtobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism.

Liyun Zhao, Liyuan Yao, Rui Chen, Jiani He, Tingting Lin, Silin Qiu, Guohua Chen, Hongfeng Chen, Sheng-Xiang Qiu.

Coronaviruses, as enveloped positive-strand RNA viruses, manipulate host lipid compositions to enable robust viral replication. Temporal modulation of the host lipid metabolism is a potential novel strategy against coronaviruses. Here, the dihydroxyflavone pinostrobin (PSB) was identified through bioassay that inhibited the increment of human coronavirus OC43 (HCoV-OC43) in human ileocecal colorectal adenocarcinoma cells. Lipid metabolomic studies showed that PSB interfered with linoleic acid and arachidonic acid metabolism pathways. PSB significantly decreased the level of 12, 13- epoxyoctadecenoic (12, 13-EpOME) and increased the level of prostaglandin E2. Interestingly, exogenous supplement of 12, 13-EpOME in HCoV-OC43-infected cells significantly stimulated HCoV-OC43 virus replication. Transcriptomic analyses showed that PSB is a negative modulator of aryl hydrocarbon receptor (AHR)/cytochrome P450 (CYP) 1A1signaling pathway and its antiviral effects can be counteracted by supplement of FICZ, a well-known AHR agonist. Integrative analyses of metabolomic and transcriptomic indicated that PSB could affect linoleic acid and arachidonic acid metabolism axis through AHR/CYP1A1 pathway. These results high light the importance of the AHR/CYP1A1 pathway and lipid metabolism in the anti-coronavirus activity of the bioflavonoid PSB.

DOI: https://doi.org/10.1016/j.antiviral.2023.105570
Viruses. 2023 Feb 13. pii: 523. [Epub ahead of print]15(2):

Oncolytic Avian Reovirus σA-Modulated Upregulation of the HIF-1α/C-myc/glut1 Pathway to Produce More Energy in Different Cancer Cell Lines Benefiting Virus Replication.

Chao-Yu Hsu, Jing-Wen Huang, Wei-Ru Huang, I-Chun Chen, Ming-Shan Chen, Tsai-Ling Liao, Yu-Kang Chang, Muhammad Munir, Hung-Jen Liu.

  Our previous reports proved that the structural protein σA of avian reovirus (ARV) is an energy activator which can regulate cellular metabolism that is essential for virus replication. This study has further demonstrated that the ARV protein σA is able to upregulate the HIF-1α/myc/glut1 pathway in three cancer cell lines (A549, B16-F10, and HeLa) to alter the metabolic pathway of host cells. Quantitative real-time RT-PCR and Western blotting results have revealed that σA protein could enhance both mRNA and the protein levels of HIF-1α, c-myc, and glut1 in these cancer cell lines. In this work, ATeam immunofluorescence staining was used to reveal that knockdown of HIF-1α, c-myc, and glut1 by shRNAs decreased cellular ATP levels. Our data reveal that the ARV σA protein can downregulate lactate fermentation and upregulate glutaminolysis. The σA protein upregulates glutaminase, which converts glutamate into the TCA cycle intermediate α-ketoglutarate, activating the TCA cycle. In the lactate fermentation pathway, ARV σA protein suppresses lactate dehydrogenase A (LDHA), implying the Warburg effect does not occur in these cancer cell lines. This study provides a novel finding revealing that ARV σA protein upregulates glycolysis and glutaminolysis to produce energy using the HIF-1α/c-myc/glut1 pathway to benefit virus replication in these cancer cell lines.

Keywords:  ATeams; HIF-1α; avian reoviruses; c-myc; glut1; glycolysis; oncolytic virus

DOI:  https://doi.org/10.3390/v15020523