bims-mevinf 2024-01-28 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024‒01‒28
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

PEDV inhibits HNRNPA3 expression by miR-218-5p to enhance cellular lipid accumulation and promote viral replication.
Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase.
Metabolic Enzymes in Viral Infection and Host Innate Immunity.
The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections.
Yellow fever virus infection in human hepatocyte cells triggers an imbalance in redox homeostasis with increased reactive oxygen species production, oxidative stress, and decreased antioxidant enzymes.
Tick-borne encephalitis virus modulates sphingolipid and phospholipid metabolism in infected human neuronal cells.
Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly.
AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4.
Gene expression profiling of host lipid metabolism in SARS-CoV-2 infected patients: a systematic review and integrated bioinformatics analysis.
NAMPT promotes the malignant progression of HBV-associated hepatocellular carcinoma through activation of SREBP1-mediated lipogenesis.

mBio. 2024 Jan 23. e0319723

PEDV inhibits HNRNPA3 expression by miR-218-5p to enhance cellular lipid accumulation and promote viral replication.

Xiaojie Shi, Qi Zhang, Naling Yang, Quanqiong Wang, Yanxia Zhang, Xingang Xu.

  Porcine epidemic diarrhea virus (PEDV) requires complete dependence on the metabolic system of the host cell to complete its life cycle. There is a strong link between efficient viral replication and cellular lipid synthesis. However, the mechanism by which PEDV interacts with host cells to hijack cellular lipid metabolism to promote its replication remains unclear. In this study, PEDV infection significantly enhanced the expression of lipid synthesis-related genes and increased cellular lipid accumulation. Furthermore, using liquid chromatography-tandem mass spectrometry, we identified heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) as the interacting molecule of PEDV NSP9. We demonstrated that the expression of HNRNPA3 was downregulated by PEDV-induced miR-218-5p through targeting its 3' untranslated region. Interestingly, knocking down HNRNPA3 facilitated the PEDV replication by promoting cellular lipid synthesis. We next found that the knockdown of HNRNPA3 potentiated the transcriptional activity of sterol regulatory element-binding transcription factor 1 (SREBF1) through zinc finger protein 135 (ZNF135) as well as PI3K/AKT and JNK signaling pathways. In summary, we propose a model in which PEDV downregulates HNRNPA3 expression to promote the expression and activation of SREBF1 and increase cellular lipid accumulation, providing a novel mechanism by which PEDV interacts with the host to utilize cellular lipid metabolism to promote its replication.IMPORTANCEAs the major components and structural basis of the viral replication complexes of positive-stranded RNA viruses, lipids play an essential role in viral replication. However, how PEDV manipulates host cell lipid metabolism to promote viral replication by interacting with cell proteins remains poorly understood. Here, we found that SREBF1 promotes cellular lipid synthesis, which is essential for PEDV replication. Moreover, HNRNPA3 negatively regulates SREBF1 activation and specifically reduces lipid accumulation, ultimately inhibiting PEDV dsRNA synthesis. Our study provides new insight into the mechanisms by which PEDV hijacks cell lipid metabolism to benefit viral replication, which can offer a potential target for therapeutics against PEDV infection.

Keywords:  HNRNPA3; PEDV; host factors; lipid; viral replication complex

DOI:  https://doi.org/10.1128/mbio.03197-23
Vet Microbiol. 2024 Jan 19. pii: S0378-1135(24)00022-1. [Epub ahead of print]290 110000

Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase.

Zicheng Ma, Lei Guo, Mengjiao Pan, Chenlong Jiang, Depeng Liu, Yanni Gao, Juan Bai, Ping Jiang, Xing Liu.

  Pseudorabies virus (PRV) is an alpha-herpesvirus capable of infecting a range of animal species, particularly its natural host, pigs, resulting in substantial economic losses for the swine industry. Recent research has shed light on the significant role of cholesterol metabolism in the replication of various viruses. However, the specific role of cholesterol metabolism in PRV infection remains unknown. Here, we demonstrated that the expression of 7-dehydrocholesterol reductase (DHCR7) is upregulated following PRV infection, as evidenced by the proteomic analysis. Subsequently, we showed that DHCR7 plays a crucial role in promoting PRV replication by converting 7-dehydrocholesterol (7-DHC) into cholesterol, leading to increased cellular cholesterol levels. Importantly, DHCR7 inhibits the phosphorylation of interferon regulatory factor 3 (IRF3), resulting in reduced levels of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs). Finally, we revealed that the DHCR7 inhibitor, trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (AY9944), significantly suppresses PRV replication both in vitro and in vivo. Taken together, the study has established a connection between cholesterol metabolism and PRV replication, offering novel insights that may guide future approaches to the prevention and treatment of PRV infections.

Keywords:  Cholesterol; DHCR7; Interferon; PRV

DOI:  https://doi.org/10.1016/j.vetmic.2024.110000
Viruses. 2023 Dec 24. pii: 35. [Epub ahead of print]16(1):

Metabolic Enzymes in Viral Infection and Host Innate Immunity.

Chao Qin, Taolin Xie, Wayne Wei Yeh, Ali Can Savas, Pinghui Feng.

  Metabolic enzymes are central players for cell metabolism and cell proliferation. These enzymes perform distinct functions in various cellular processes, such as cell metabolism and immune defense. Because viral infections inevitably trigger host immune activation, viruses have evolved diverse strategies to blunt or exploit the host immune response to enable viral replication. Meanwhile, viruses hijack key cellular metabolic enzymes to reprogram metabolism, which generates the necessary biomolecules for viral replication. An emerging theme arising from the metabolic studies of viral infection is that metabolic enzymes are key players of immune response and, conversely, immune components regulate cellular metabolism, revealing unexpected communication between these two fundamental processes that are otherwise disjointed. This review aims to summarize our present comprehension of the involvement of metabolic enzymes in viral infections and host immunity and to provide insights for potential antiviral therapy targeting metabolic enzymes.

Keywords:  antiviral therapy; cell metabolism; inflammatory response; innate immunity; interferon; metabolic enzymes; viral infection

DOI:  https://doi.org/10.3390/v16010035
Pathogens. 2023 Dec 31. pii: 39. [Epub ahead of print]13(1):

The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections.

Maria Daskou, Leila Fotooh Abadi, Chandrima Gain, Michael Wong, Eashan Sharma, Arnaud John Kombe Kombe, Ravikanth Nanduri, Theodoros Kelesidis.

  In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.

Keywords:  NRF2 pathway; inflammation; respiratory viruses; viral replication

DOI:  https://doi.org/10.3390/pathogens13010039
Free Radic Biol Med. 2024 Jan 24. pii: S0891-5849(24)00050-9. [Epub ahead of print]

Yellow fever virus infection in human hepatocyte cells triggers an imbalance in redox homeostasis with increased reactive oxygen species production, oxidative stress, and decreased antioxidant enzymes.

Ariane Coelho Ferraz, Marília Bueno da Silva Menegatto, Rafaela Lameira Souza Lima, Oluwashola Samuel Ola-Olub, Daniela Caldeira Costa, José Carlos de Magalhães, Izabela Maurício Rezende, Angelle Desiree LaBeaud, Thomas P Monath, Pedro Augusto Alves, Andréa Teixeira de Carvalho, Olindo Assis Martins-Filho, Betânia P Drumond, Cintia Lopes de Brito Magalhães.

  Yellow fever (YF) presents a wide spectrum of severity, with clinical manifestations in humans ranging from febrile and self-limited to fatal cases. Although YF is an old disease for which an effective and safe vaccine exists, little is known about the viral- and host-specific mechanisms that contribute to liver pathology. Several studies have demonstrated that oxidative stress triggered by viral infections contributes to pathogenesis. We evaluated whether yellow fever virus (YFV), when infecting human hepatocytes cells, could trigger an imbalance in redox homeostasis, culminating in oxidative stress. YFV infection resulted in a significant increase in reactive oxygen species (ROS) levels from 2 to 4 days post infection (dpi). When measuring oxidative parameters at 4 dpi, YFV infection caused oxidative damage to lipids, proteins, and DNA, evidenced by an increase in lipid peroxidation/8-isoprostane, carbonyl protein, and 8-hydroxy-2'-deoxyguanosine, respectively. Furthermore, there was a significant reduction in the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), in addition to a reduction in the ratio of reduced to oxidized glutathione (GSH/GSSG), indicating a pro-oxidant environment. However, no changes were observed in the enzymatic activity of the enzyme catalase (CAT) or in the gene expression of SOD isoforms (1/2/3), CAT, or GPx. Therefore, our results show that YFV infection generates an imbalance in redox homeostasis, with the overproduction of ROS and depletion of antioxidant enzymes, which induces oxidative damage to cellular constituents. Moreover, as it has been demonstrated that oxidative stress is a conspicuous event in YFV infection, therapeutic strategies based on antioxidant biopharmaceuticals may be new targets for the treatment of YF.

Keywords:  Antioxidant defenses; Pathogenesis; Reactive oxygen species; Redox homeostasis; Yellow fever virus

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.042
Microbes Infect. 2024 Jan 24. pii: S1286-4579(24)00023-6. [Epub ahead of print] 105303

Tick-borne encephalitis virus modulates sphingolipid and phospholipid metabolism in infected human neuronal cells.

Pavlína Šimečková, Josef Slavík, Andrea Fořtová, Ivana Huvarová, Lucie Králiková, Michal Stefanik, Pavel Svoboda, Daniel Ruzek, Miroslav Machala.

  The life cycle of enveloped viruses is closely linked to host-cell lipids. However, changes in lipid metabolism during infections with the tick-borne encephalitis virus (TBEV) have not been described. TBEV is a medically important orthoflavivirus, which is endemic to many parts of Europe and Asia. In the present study, we performed targeted lipidomics with HPLC-MS/MS to evaluate changes in phospholipid and sphingolipid concentrations in TBEV-infected human neuronal SK-N-SH cells. TBEV infections significantly increased phosphatidylcholine, phosphatidylinositol, and phosphatidylserine levels within 48 h post-infection (hpi). Sphingolipids were slightly increased in dihydroceramides within 24 hpi. Later, at 48 hpi, the contents of sphinganine, dihydroceramides, ceramides, glucosylceramides, and ganglioside GD3 were elevated. On the other hand, sphingosine-1-phosphate content was slightly reduced in TBEV-infected cells. Changes in sphingolipid concentrations were accompanied by suppressed expression of a majority of the genes linked to sphingolipid and glycosphingolipid metabolism. Furthermore, we found that a pharmacological inhibitor of sphingolipid synthesis, fenretinide (4-HPR), inhibited TBEV infections in SK-N-SH cells. Taken together, our results suggested that both structural and signaling functions of lipids could be affected during TBEV infections. These changes might be connected to virus propagation and/or host-cell defense.

Keywords:  4-HPR; fenretinide; human neuronal cells; sphingolipids; targeted lipidomics; tick-borne encephalitis virus

DOI:  https://doi.org/10.1016/j.micinf.2024.105303
Nat Commun. 2024 Jan 20. 15(1): 640

Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly.

Emilie Murigneux, Laurent Softic, Corentin Aubé, Carmen Grandi, Delphine Judith, Johanna Bruce, Morgane Le Gall, François Guillonneau, Alain Schmitt, Vincent Parissi, Clarisse Berlioz-Torrent, Laurent Meertens, Maike M K Hansen, Sarah Gallois-Montbrun.

Considerable progress has been made in understanding the molecular host-virus battlefield during SARS-CoV-2 infection. Nevertheless, the assembly and egress of newly formed virions are less understood. To identify host proteins involved in viral morphogenesis, we characterize the proteome of SARS-CoV-2 virions produced from A549-ACE2 and Calu-3 cells, isolated via ultracentrifugation on sucrose cushion or by ACE-2 affinity capture. Bioinformatic analysis unveils 92 SARS-CoV-2 virion-associated host factors, providing a valuable resource to better understand the molecular environment of virion production. We reveal that G3BP1 and G3BP2 (G3BP1/2), two major stress granule nucleators, are embedded within virions and unexpectedly favor virion production. Furthermore, we show that G3BP1/2 participate in the formation of cytoplasmic membrane vesicles, that are likely virion assembly sites, consistent with a proviral role of G3BP1/2 in SARS-CoV-2 dissemination. Altogether, these findings provide new insights into host factors required for SARS-CoV-2 assembly with potential implications for future therapeutic targeting.

DOI: https://doi.org/10.1038/s41467-024-44958-0
Viruses. 2024 Jan 04. pii: 82. [Epub ahead of print]16(1):

AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4.

Isabella Spinello, Ernestina Saulle, Maria Teresa Quaranta, Elvira Pelosi, Germana Castelli, Annamaria Cerio, Luca Pasquini, Ornella Morsilli, Maria Luisa Dupuis, Catherine Labbaye.

  Coagulation disorders are described in COVID-19 and long COVID patients. In particular, SARS-CoV-2 infection in megakaryocytes, which are precursors of platelets involved in thrombotic events in COVID-19, long COVID and, in rare cases, in vaccinated individuals, requires further investigation, particularly with the emergence of new SARS-CoV-2 variants. CD147, involved in the regulation of inflammation and required to fight virus infection, can facilitate SARS-CoV-2 entry into megakaryocytes. MCT4, a co-binding protein of CD147 and a key player in the glycolytic metabolism, could also play a role in SARS-CoV-2 infection. Here, we investigated the susceptibility of megakaryocytes to SARS-CoV-2 infection via CD147 and MCT4. We performed infection of Dami cells and human CD34+ hematopoietic progenitor cells induced to megakaryocytic differentiation with SARS-CoV-2 pseudovirus in the presence of AC-73 and syrosingopine, respective inhibitors of CD147 and MCT4 and inducers of autophagy, a process essential in megakaryocyte differentiation. Both AC-73 and syrosingopine enhance autophagy during differentiation but only AC-73 enhances megakaryocytic maturation. Importantly, we found that AC-73 or syrosingopine significantly inhibits SARS-CoV-2 infection of megakaryocytes. Altogether, our data indicate AC-73 and syrosingopine as inhibitors of SARS-CoV-2 infection via CD147 and MCT4 that can be used to prevent SARS-CoV-2 binding and entry into megakaryocytes, which are precursors of platelets involved in COVID-19-associated coagulopathy.

Keywords:  CD147; MCT4; SARS-CoV-2; coagulation disorders; megakaryocytes

DOI:  https://doi.org/10.3390/v16010082
BMC Infect Dis. 2024 Jan 23. 24(1): 124

Gene expression profiling of host lipid metabolism in SARS-CoV-2 infected patients: a systematic review and integrated bioinformatics analysis.

Wan Amirul Syazwan Wan Ahmad Munawar, Marjanu Hikmah Elias, Faizul Helmi Addnan, Pouya Hassandarvish, Sazaly AbuBakar, Nuruliza Roslan.

  BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic occurred due to the dispersion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe symptoms can be observed in COVID-19 patients with lipid-related comorbidities such as obesity and diabetes. Yet, the extensive molecular mechanisms of how SARS-CoV-2 causes dysregulation of lipid metabolism remain unknown.METHODS: Here, an advanced search of articles was conducted using PubMed, Scopus, EBSCOhost, and Web of Science databases using terms from Medical Subject Heading (MeSH) like SARS-CoV-2, lipid metabolism and transcriptomic as the keywords. From 428 retrieved studies, only clinical studies using next-generation sequencing as a gene expression method in COVID-19 patients were accepted. Study design, study population, sample type, the method for gene expression and differentially expressed genes (DEGs) were extracted from the five included studies. The DEGs obtained from the studies were pooled and analyzed using the bioinformatics software package, DAVID, to determine the enriched pathways. The DEGs involved in lipid metabolic pathways were selected and further analyzed using STRING and Cytoscape through visualization by protein-protein interaction (PPI) network complex.
RESULTS: The analysis identified nine remarkable clusters from the PPI complex, where cluster 1 showed the highest molecular interaction score. Three potential candidate genes (PPARG, IFITM3 and APOBEC3G) were pointed out from the integrated bioinformatics analysis in this systematic review and were chosen due to their significant role in regulating lipid metabolism. These candidate genes were significantly involved in enriched lipid metabolic pathways, mainly in regulating lipid homeostasis affecting the pathogenicity of SARS-CoV-2, specifically in mechanisms of viral entry and viral replication in COVID-19 patients.
CONCLUSIONS: Taken together, our findings in this systematic review highlight the affected lipid-metabolic pathways along with the affected genes upon SARS-CoV-2 invasion, which could be a potential target for new therapeutic strategies study in the future.

Keywords:  Bioinformatics; Gene expression; Lipid metabolism; Next-generation sequencing; SARS-CoV-2

DOI:  https://doi.org/10.1186/s12879-024-08983-0
FASEB J. 2024 Jan 31. 38(2): e23444

NAMPT promotes the malignant progression of HBV-associated hepatocellular carcinoma through activation of SREBP1-mediated lipogenesis.

Xian-Lu He, Hui-Jie Guo, Ya-Ruo Lei, Jun Li, Jing-Yi Li, Min-Hui Li, Na Li, Fei Wang, Chun-Fen Mo.

  Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.

Keywords:  HCC; NAMPT; SREBP1; hepatitis B virus; lipogenesis

DOI:  https://doi.org/10.1096/fj.202300070RRR