bims-mevinf 2023-07-02 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–07–02
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Infectious Bursal Disease Virus Assembly Causes Endoplasmic Reticulum Stress and Lipid Droplet Accumulation.
Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis.
Risk Factors for Glucose 6-Phosphate Dehydrogenase and COVID-19 Disease-A Retrospective Study at a Major Saudi Tertiary Center.
Cytokine storm associated with severe COVID-19 infections: The potential mitigating role of omega-3 fatty acid triglycerides in the ICU.
Lipid signatures of West Nile virus infection unveil alterations of sphingolipid metabolism providing novel biomarkers.
Theaflavin inhibits African swine fever virus replication by disrupting lipid metabolism through activation of the AMPK signaling pathway in virto.
Inhibition of PERK Kinase, an Orchestrator of the Unfolded Protein Response (UPR), Significantly Reduces Apoptosis and Inflammation of Lung Epithelial Cells Triggered by SARS-CoV-2 ORF3a Protein.
Genetic and Epigenetic Host-Virus Network to Investigate Pathogenesis and Identify Biomarkers for Drug Repurposing of Human Respiratory Syncytial Virus via Real-World Two-Side RNA-Seq Data: Systems Biology and Deep-Learning Approach.

Viruses. 2023 05 31. pii: 1295. [Epub ahead of print]15(6):

Infectious Bursal Disease Virus Assembly Causes Endoplasmic Reticulum Stress and Lipid Droplet Accumulation.

Yesica R Frontini-López, Lautaro Rivera, Cristian A Pocognoni, Julieta S Roldán, María I Colombo, Marina Uhart, Laura R Delgui.

  Gumboro illness is caused by the highly contagious immunosuppressive infectious bursal disease virus (IBDV), which affects the poultry industry globally. We have previously shown that IBDV hijacks the endocytic pathway to construct viral replication complexes on endosomes linked to the Golgi complex (GC). Then, analyzing crucial proteins involved in the secretory pathway, we showed the essential requirement of Rab1b, the Rab1b downstream effector Golgi-specific BFA resistance factor 1 (GBF1), and its substrate, the small GTPase ADP-ribosylation factor 1 (ARF1), for IBDV replication. In the current work, we focused on elucidating the IBDV assembly sites. We show that viral assembly occurs within single-membrane compartments closely associated with endoplasmic reticulum (ER) membranes, though we failed to elucidate the exact nature of the virus-wrapping membranes. Additionally, we show that IBDV infection promotes the stress of the ER, characterized by an accumulation of the chaperone binding protein (BiP) and lipid droplets (LDs) in the host cells. Overall, our results represent further original data showing the interplay between IBDV and the secretory pathway, making a substantial contribution to the field of birnaviruses-host cell interactions.

Keywords:  assembly; endoplasmic reticulum; infectious bursal disease virus; lipid droplets

DOI:  https://doi.org/10.3390/v15061295
Virology. 2023 Jun 21. pii: S0042-6822(23)00134-4. [Epub ahead of print]585 196-204

Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis.

Yoya Vashi, Ganesh Nehru, Sachin Kumar.

  Newcastle disease virus (NDV), a member of Paramyxoviridae family, is one of the most important pathogens in poultry. To ensure optimal environments for their replication and spread, viruses rely largely on host cellular metabolism. In the present study, we evaluated the small drug molecule niclosamide for its anti-NDV activity. Our study has shown that a sublethal dose of 1 μM niclosamide could drastically reduce NDV replication. The results showed that niclosamide has antiviral activity against NDV infection during in vitro, in ovo and in vivo assays. Pharmacologically inhibiting the glycolytic pathway remarkably reduced NDV RNA synthesis and infectious virion production. Our results suggest that the effect of niclosamide on cellular glycolysis could be the possible reason for the specific anti-NDV effect. This study could help us understand antiviral strategies against similar pathogens and may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways.

Keywords:  Anti-viral; Glycolysis; Newcastle disease virus; Niclosamide

DOI:  https://doi.org/10.1016/j.virol.2023.06.010
Viruses. 2023 05 23. pii: 1224. [Epub ahead of print]15(6):

Risk Factors for Glucose 6-Phosphate Dehydrogenase and COVID-19 Disease-A Retrospective Study at a Major Saudi Tertiary Center.

Badi A Alotaibi, Jehad A Aldali, Hamzah J Aldali, Glowi A Alasiri, Emadeldin M Elsokkary, Areej Al Mugairi, Abdulaziz M Almuqrin.

  Glucose-6-phosphate dehydrogenase (G6PD) insufficiency is a common enzymatic defect worldwide; it affects over 400 million people and is associated with various disorders. Recent research suggests that G6PD-deficient cells are susceptible to infection by human coronaviruses, as the G6PD enzyme is involved in the metabolism of oxidative stress, which may enhance COVID-19 mortality. This retrospective study aimed to examine the effect of COVID-19 on patients with G6PD deficiency by comparing the laboratory parameters of patients with G6PD enzyme deficiency alone, COVID-19 alone, and those with both COVID-19 and G6PD enzyme deficiency treated at a major Saudi tertiary center. The results indicated significant differences in hematological and biochemical parameters between the three patient groups, indicating that COVID-19 may influence these parameters, and that they could be used to measure the severity of COVID-19 disease. Moreover, this study suggests that patients with G6PD enzyme deficiency may be at higher risk for severe COVID-19 outcomes. Although the study is limited by the lack of a random selection method for group membership, the Kruskal-Wallis H-test was used to statistical assess the data. The study's findings can enhance the understanding of the relation between COVID-19 infected and G6PD-deficiency patients and inform clinical decision making for an improved patient outcome.

Keywords:  COVID-19; biochemical parameters; glucose-6-phosphate dehydrogenase (G6PD); hematological; oxidative stress metabolism

DOI:  https://doi.org/10.3390/v15061224
FASEB J. 2023 Aug;37(8): e23066

Cytokine storm associated with severe COVID-19 infections: The potential mitigating role of omega-3 fatty acid triglycerides in the ICU.

David F Driscoll, Bruce R Bistrian.

  Cytokine storm during severe COVID-19 infection increases the risk of mortality in critically ill patients in the intensive care unit. Multiple therapeutic proposals include, for example, anti-inflammatory and immunosuppressive agents, selective inhibitors of key pro-inflammatory receptors, and key enzymes necessary for viral replication. Unfortunately, safe and effective therapy remains an elusive goal. An alternative anti-inflammatory approach vis á vis omega-3 fatty acids, which yields less pro-inflammatory mediators by altering eicosanoid metabolism, has been proposed. Although theoretically promising, enteral tube delivery or oral capsules containing specific doses of omega-3 fatty acids take precious time (7 days to 6 weeks) to be incorporated in plasma cell membranes to be most effective, making this route of administration in the acute care setting an unfeasible therapeutic approach. Parenteral administration of precise doses of omega-3 fatty acid triglycerides in an injectable emulsion can greatly accelerate the incorporation and potential therapeutic effects (within hours), but at present, there is no commercially available product designed for this purpose. We describe a potential formulation that may address this deficiency, while recognizing that the high incidence of hyperlipidemia that occurs during severe COVID-19 infection must be recognized as a complicating factor, and, therefore, caution is advised.

Keywords:  COVID-19 infection; cytokine storm; eicosanoid signaling; hypertriglyceridemia; lipid mediators; omega-3 fatty acids

DOI:  https://doi.org/10.1096/fj.202300396R
Emerg Microbes Infect. 2023 Jun 28. 2231556

Lipid signatures of West Nile virus infection unveil alterations of sphingolipid metabolism providing novel biomarkers.

Patricia Mingo-Casas, Javier Sanchez-Céspedes, Ana-Belén Blázquez, Josefina Casas, María Balsera-Manzanero, Lura Herrero, Ana Vázquez, Jerónimo Pachón, Manuela Aguilar-Guisado, José Miguel Cisneros, Juan-Carlos Saiz, Miguel A Martín-Acebes.

  West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bites of infected mosquitoes. Severe forms of West Nile disease (WND) can curse with meningitis, encephalitis or acute flaccid paralysis. A better understanding of the physiopathology associated with disease progression is mandatory to find biomarkers and effective therapies. In this scenario, blood derivatives (plasma and serum) constitute the more commonly used biofluids due to its ease of collection and high value for diagnostic purposes. Therefore, the potential impact of this virus in the circulating lipidome was addressed combining the analysis of samples from experimentally infected mice and naturally WND patients. Our results unveil dynamic alterations in the lipidome that define specific metabolic fingerprints of different infection stages. Concomitant with neuroinvasion in mice, the lipid landscape was dominated by a metabolic reprograming that resulted in significant elevations of circulating sphingolipids (ceramides, dihydroceramides and dihydrosphingomyelins), phosphatidylethanolamines and triacylglycerols. Remarkably, patients suffering from WND also displayed an elevation of ceramides, dihydroceramides, lactosylceramides and monoacylglycerols in their sera. The dysregulation of sphingolipid metabolism by WNV may provide new therapeutic opportunities and supports the potential of certain lipids as novel peripheral biomarkers of WND progression.

Keywords:  West Nile virus; biomarker; lipid; patient; viral infection

DOI:  https://doi.org/10.1080/22221751.2023.2231556
Virus Res. 2023 Jun 27. pii: S0168-1702(23)00121-1. [Epub ahead of print] 199159

Theaflavin inhibits African swine fever virus replication by disrupting lipid metabolism through activation of the AMPK signaling pathway in virto.

Yang Chen, Zhi Wei, Zebu Song, Hao Chang, Yanchen Guo, Yankuo Sun, Heng Wang, Zezhong Zheng, Guihong Zhang.

  African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), which is one of the most harmful swine diseases in the pig industry because of its nearly 100% mortality rate in domestic pigs and results in incalculable economic loss. Ever since ASF was initially reported, scientists have worked to develop anti-ASF vaccines; however, currently no clinically effective vaccine for ASF is available. Therefore, the development of novel measures to prevent ASFV infection and transmission is essential. In this study, we aimed to investigate the anti-ASF activity of theaflavin (TF), a natural compound mainly isolated from black tea. We found that TF potently inhibited ASFV replication at non-cytotoxic concentrations ex vivo in primary porcine alveolar macrophages (PAMs). Mechanistically, we found that TF inhibited ASFV replication by acting on cells rather than interacting directly with ASFV to inhibit viral replication. Further, we found that TF upregulated the AMPK (5'-AMP-activated protein kinase) signaling pathway in ASFV-infected and uninfected cells, and treatment with the AMPK agonist MK8722 upregulated the AMPK signaling pathway and inhibited ASFV proliferation in a dose-dependent manner. Notably, the effects of TF on AMPK activation and ASFV inhibition were partially reversed by the AMPK inhibitor dorsomorphin. In addition, we found that TF down-regulated the expression of genes related to lipid synthesis and decreased the intracellular accumulation of total cholesterol and total triglycerides in ASFV-infected cells, suggesting that TF may inhibit ASFV replication by disrupting lipid metabolism. In summary, our results demonstrated that TF is an ASFV infection inhibitor and revealed the mechanism by which ASFV replication is inhibited, providing a novel mechanism and potential lead compound for the development of anti-ASFV drugs.

Keywords:  AMPK signaling pathway; African swine fever virus; lipid metabolism; theaflavin

DOI:  https://doi.org/10.1016/j.virusres.2023.199159
Biomedicines. 2023 May 30. pii: 1585. [Epub ahead of print]11(6):

Inhibition of PERK Kinase, an Orchestrator of the Unfolded Protein Response (UPR), Significantly Reduces Apoptosis and Inflammation of Lung Epithelial Cells Triggered by SARS-CoV-2 ORF3a Protein.

Panagiotis Keramidas, Eleni Papachristou, Rigini M Papi, Aglaia Mantsou, Theodora Choli-Papadopoulou.

  SARS-CoV-2 ORF3a accessory protein was found to be involved in virus release, immunomodulation and exhibited a pro-apoptotic character. In order to unravel a potential ORF3a-induced apoptotic and inflammatory death mechanism, lung epithelial cells (A549) were transfected with in vitro synthesized ORF3a mRNA. The protein's dynamic involvement as "stress factor" for the endoplasmic reticulum, causing the activation of PERK kinase and other UPR-involved proteins and therefore the upregulation of their signaling pathway executioners (ATF6, XBP-1s, PERK, phospho eIF2a, ATF4, CHOP, GADD34), has been clearly demonstrated. Furthermore, the overexpression of BAX and BH3-only pro-apoptotic protein PUMA, the upregulation of Bcl-2 family genes (BAX, BAK, BID, BAD), the reduced expression of Bcl-2 in mRNA and protein levels, and lastly, the cleavage of PARP-1 and caspase family members (caspase-3,-8 and -9) indicate that ORF3a displays its apoptotic character through the mitochondrial pathway of apoptosis. Moreover, the upregulation of NFκB, phosphorylation of p65 and IκΒα and the elevated expression of pro-inflammatory cytokines (IL-1b, IL-6, IL-8 and IL-18) in transfected cells with ORF3a mRNA indicate that this protein causes the inflammatory response through NFκB activation and therefore triggers lung injury. An intriguing finding of our study is that upon treatment of the ORF3a-transfected cells with GSK2606414, a selective PERK inhibitor, both complications (apoptosis and inflammatory response) were neutralized, and cell survival was favored, whereas treatment of transfected cells with z-VAD (a pan-caspase inhibitor) despite inhibiting cell death, could not ameliorate the inflammatory response of transfected A549 cells. Given the above, we point out that PERK kinase is a "master tactician" and its activation constitutes the main stimulus for the emergence of ORF3a apoptotic and inflammatory nature and therefore could serve as potential target for developing novel therapeutic approaches against COVID-19.

Keywords:  ER stress; GSK2606414; ORF3a; PERK; SARS-CoV-2; apoptosis; cytokine storm; inflammation; pyroptosis

DOI:  https://doi.org/10.3390/biomedicines11061585
Biomedicines. 2023 May 25. pii: 1531. [Epub ahead of print]11(6):

Genetic and Epigenetic Host-Virus Network to Investigate Pathogenesis and Identify Biomarkers for Drug Repurposing of Human Respiratory Syncytial Virus via Real-World Two-Side RNA-Seq Data: Systems Biology and Deep-Learning Approach.

Bo-Wei Hsu, Bor-Sen Chen.

  Human respiratory syncytial virus (hRSV) affects more than 33 million people each year, but there are currently no effective drugs or vaccines approved. In this study, we first constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via big-data mining. Then, we employed reversed dynamic methods via two-side host-pathogen RNA-seq time-profile data to prune false positives in candidate HPI-GWGEN to obtain the real HPI-GWGEN. With the aid of principal-network projection and the annotation of KEGG pathways, we can extract core signaling pathways during hRSV infection to investigate the pathogenic mechanism of hRSV infection and select the corresponding significant biomarkers as drug targets, i.e., TRAF6, STAT3, IRF3, TYK2, and MAVS. Finally, in order to discover potential molecular drugs, we trained a DNN-based DTI model by drug-target interaction databases to predict candidate molecular drugs for these drug targets. After screening these candidate molecular drugs by three drug design specifications simultaneously, i.e., regulation ability, sensitivity, and toxicity. We finally selected acitretin, RS-67333, and phenformin to combine as a potential multimolecule drug for the therapeutic treatment of hRSV infection.

Keywords:  DNN-based DTI model; HPI-GWGEN; KEGG pathways; drug design specification; host–pathogen RNA-Seq data; human respiratory syncytial virus (hRSV); multimolecule drug; system biology

DOI:  https://doi.org/10.3390/biomedicines11061531