bims-mevinf 2024-05-05 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–05–05
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

From Glycolysis to Viral Defense: The Multifaceted Impact of Glycolytic Enzymes on Human Immunodeficiency Virus Type 1 Replication.
Critical role of G3BP1 in bovine parainfluenza virus type 3 (BPIV3)-inhibition of stress granules formation and viral replication.
Inhibition of NADPH oxidase 2 enhances resistance to viral neuroinflammation by facilitating M1-polarization of macrophages at the extraneural tissues.
Oxidative stress in patients with coronavirus disease and end-stage renal disease: a pilot study.
Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne.
Redox Biomarkers - An Effective Tool for Diagnosing COVID-19 Patients and Convalescents.
Metformin as adjuvant treatment in hepatitis C virus infections and associated complications.
The severity of COVID-19 upon hospital admission is associated with plasma omega-3 fatty acids.

Biol Pharm Bull. 2024 ;47(5): 905-911

From Glycolysis to Viral Defense: The Multifaceted Impact of Glycolytic Enzymes on Human Immunodeficiency Virus Type 1 Replication.

Naoki Kishimoto, Shogo Misumi.

  Viruses require host cells to replicate and proliferate, which indicates that viruses hijack the cellular machinery. Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4-positive T cells, and efficiently uses cellular proteins to replicate. Cells already have proteins that inhibit the replication of the foreign HIV-1, but their function is suppressed by viral proteins. Intriguingly, HIV-1 infection also changes the cellular metabolism to aerobic glycolysis. This phenomenon has been interpreted as a cellular response to maintain homeostasis during viral infection, yet HIV-1 efficiently replicates even in this environment. In this review, we discuss the regulatory role of glycolytic enzymes in viral replication and the impact of aerobic glycolysis on viral infection by introducing various host proteins involved in viral replication. Furthermore, we would like to propose a "glyceraldehyde-3-phosphate dehydrogenase-induced shock (G-shock) and kill strategy" that maximizes the antiviral effect of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to eliminate latently HIV-1-infected cells.

Keywords:  aerobic glycolysis; antiviral protein; human immunodeficiency virus type 1; moonlighting protein

DOI:  https://doi.org/10.1248/bpb.b23-00605
Front Immunol. 2024 ;15 1358036

Critical role of G3BP1 in bovine parainfluenza virus type 3 (BPIV3)-inhibition of stress granules formation and viral replication.

Nian Liu, Wei Yang, Lingzhi Luo, Mingshuang Ma, Jin Cui, Xiumei Dong, Yijing Li.

   Background: It remains unclear whether BPIV3 infection leads to stress granules formation and whether G3BP1 plays a role in this process and in viral replication. This study aims to clarify the association between BPIV3 and stress granules, explore the effect of G3BP1 on BPIV3 replication, and provide significant insights into the mechanisms by which BPIV3 evades the host's antiviral immunity to support its own survival.
Methods: Here, we use Immunofluorescence staining to observe the effect of BPIV3 infection on the assembly of stress granules. Meanwhile, the expression changes of eIF2α and G3BP1 were determined. Overexpression or siRNA silencing of intracellular G3BP1 levels was examined for its regulatory control of BPIV3 replication.
Results: We identify that the BPIV3 infection elicited phosphorylation of the eIF2α protein. However, it did not induce the assembly of stress granules; rather, it inhibited the formation of stress granules and downregulated the expression of G3BP1. G3BP1 overexpression facilitated the formation of stress granules within cells and hindered viral replication, while G3BP1 knockdown enhanced BPIV3 expression.
Conclusion: This study suggest that G3BP1 plays a crucial role in BPIV3 suppressing stress granule formation and viral replication.

Keywords:  BPIV3; G3BP1; inhibition; stress granules; viral replication

DOI:  https://doi.org/10.3389/fimmu.2024.1358036
J Neuroinflammation. 2024 May 02. 21(1): 115

Inhibition of NADPH oxidase 2 enhances resistance to viral neuroinflammation by facilitating M1-polarization of macrophages at the extraneural tissues.

Jin Young Choi, Hee Won Byeon, Seong Ok Park, Erdenebileg Uyangaa, Koanhoi Kim, Seong Kug Eo.

   BACKGROUND: Macrophages play a pivotal role in the regulation of Japanese encephalitis (JE), a severe neuroinflammation in the central nervous system (CNS) following infection with JE virus (JEV). Macrophages are known for their heterogeneity, polarizing into M1 or M2 phenotypes in the context of various immunopathological diseases. A comprehensive understanding of macrophage polarization and its relevance to JE progression holds significant promise for advancing JE control and therapeutic strategies.
METHODS: To elucidate the role of NADPH oxidase-derived reactive oxygen species (ROS) in JE progression, we assessed viral load, M1 macrophage accumulation, and cytokine production in WT and NADPH oxidase 2 (NOX2)-deficient mice using murine JE model. Additionally, we employed bone marrow (BM) cell-derived macrophages to delineate ROS-mediated regulation of macrophage polarization by ROS following JEV infection.
RESULTS: NOX2-deficient mice exhibited increased resistance to JE progression rather than heightened susceptibility, driven by the regulation of macrophage polarization. These mice displayed reduced viral loads in peripheral lymphoid tissues and the CNS, along with diminished infiltration of inflammatory cells into the CNS, thereby resulting in attenuated neuroinflammation. Additionally, NOX2-deficient mice exhibited enhanced JEV-specific Th1 CD4 + and CD8 + T cell responses and increased accumulation of M1 macrophages producing IL-12p40 and iNOS in peripheral lymphoid and inflamed extraneural tissues. Mechanistic investigations revealed that NOX2-deficient macrophages displayed a more pronounced differentiation into M1 phenotypes in response to JEV infection, thereby leading to the suppression of viral replication. Importantly, the administration of H2O2 generated by NOX2 was shown to inhibit M1 macrophage polarization. Finally, oral administration of the ROS scavenger, butylated hydroxyanisole (BHA), bolstered resistance to JE progression and reduced viral loads in both extraneural tissues and the CNS, along with facilitated accumulation of M1 macrophages.
CONCLUSION: In light of our results, it is suggested that ROS generated by NOX2 play a role in undermining the control of JEV replication within peripheral extraneural tissues, primarily by suppressing M1 macrophage polarization. Subsequently, this leads to an augmentation in the viral load invading the CNS, thereby facilitating JE progression. Hence, our findings ultimately underscore the significance of ROS-mediated macrophage polarization in the context of JE progression initiated JEV infection.

Keywords:  Japanese encephalitis; Macrophages; NADPH oxidase 2; ROS scavenger; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12974-024-03078-8
BMC Nephrol. 2024 May 04. 25(1): 155

Oxidative stress in patients with coronavirus disease and end-stage renal disease: a pilot study.

Nam-Seon Beck, Yeonju Seo, Taesung Park, Sang-Sin Jun, Joung-Il Im, Sae-Yong Hong.

   BACKGROUND: Oxidative stress, an imbalance between reactive oxygen species production and antioxidant capacity, increases in patients with coronavirus disease (COVID-19) or renal impairment. We investigated whether combined COVID-19 and end-stage renal disease (ESRD) would increase oxidative stress levels compared to each disease alone.
METHODS: Oxidative stress was compared among three groups. Two groups comprised patients with COVID-19 referred to the hospital with or without renal impairment (COVID-ESRD group [n = 18]; COVID group [n = 17]). The third group (ESRD group [n = 18]) comprised patients without COVID-19 on maintenance hemodialysis at a hospital.
RESULTS: The total oxidative stress in the COVID-ESRD group was lower than in the COVID group (p = 0.047). The total antioxidant status was higher in the COVID-ESRD group than in the ESRD (p < 0.001) and COVID (p < 0.001) groups after controlling for covariates. The oxidative stress index was lower in the COVID-ESRD group than in the ESRD (p = 0.001) and COVID (p < 0.001) groups. However, the three oxidative parameters did not differ significantly between the COVID and COVID-ESRD groups.
CONCLUSIONS: The role of reactive oxygen species in the pathophysiology of COVID-19 among patients withESRD appears to be non-critical. Therefore, the provision of supplemental antioxidants may not confer a therapeutic advantage, particularly in cases of mild COVID-19 in ESRD patients receiving hemodialysis. Nonetheless, this area merits further research.

Keywords:  COVID-19; End-stage renal disease; Hemodialysis; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12882-024-03584-0
Biol Pharm Bull. 2024 ;47(5): 930-940

Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne.

Mana Murae, Shota Sakai, Non Miyata, Yoshimi Shimizu, Yuko Okemoto-Nakamura, Takuma Kishimoto, Motohiko Ogawa, Hideki Tani, Kazuma Tanaka, Kohji Noguchi, Masayoshi Fukasawa.

  The coronavirus disease 2019 (COVID-19) is caused by the etiological agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19, with the recurrent epidemics of new variants of SARS-CoV-2, remains a global public health problem, and new antivirals are still required. Some cholesterol derivatives, such as 25-hydroxycholesterol, are known to have antiviral activity against a wide range of enveloped and non-enveloped viruses, including SARS-CoV-2. At the entry step of SARS-CoV-2 infection, the viral envelope fuses with the host membrane dependent of viral spike (S) glycoproteins. From the screening of cholesterol derivatives, we found a new compound 26,27-dinorcholest-5-en-24-yne-3β,20-diol (Nat-20(S)-yne) that inhibited the SARS-CoV-2 S protein-dependent membrane fusion in a syncytium formation assay. Nat-20(S)-yne exhibited the inhibitory activities of SARS-CoV-2 pseudovirus entry and intact SARS-CoV-2 infection in a dose-dependent manner. Among the variants of SARS-CoV-2, inhibition of infection by Nat-20(S)-yne was stronger in delta and Wuhan strains, which predominantly invade into cells via fusion at the plasma membrane, than in omicron strains. The interaction between receptor-binding domain of S proteins and host receptor ACE2 was not affected by Nat-20(S)-yne. Unlike 25-hydroxycholesterol, which regulates various steps of cholesterol metabolism, Nat-20(S)-yne inhibited only de novo cholesterol biosynthesis. As a result, plasma membrane cholesterol content was substantially decreased in Nat-20(S)-yne-treated cells, leading to inhibition of SARS-CoV-2 infection. Nat-20(S)-yne having a new mechanism of action may be a potential therapeutic candidate for COVID-19.

Keywords:  26,27-dinorcholest-5-en-24-yne-3β,20-diol (Nat-20(S)-yne); antiviral; cholesterol; cholesterol biosynthesis; coronavirus disease 2019 (COVID-19); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

DOI:  https://doi.org/10.1248/bpb.b23-00797
J Inflamm Res. 2024 ;17 2589-2607

Redox Biomarkers - An Effective Tool for Diagnosing COVID-19 Patients and Convalescents.

Blanka Wolszczak-Biedrzycka, Justyna Dorf, Joanna Matowicka-Karna, Violetta Dymicka-Piekarska, Marzena Wojewódzka-Żeleźniakowicz, Piotr Żukowski, Anna Zalewska, Łukasz Dąbrowski, Mateusz Maciejczyk.

   Aim: COVID-19 triggers the overproduction of reactive oxygen species (ROS) which, in combination with a weakened antioxidant barrier, can lead to protein oxidation and lipid peroxidation. The aim of this study was to evaluate enzymatic and non-enzymatic antioxidants, the overall redox potential, and protein and lipid peroxidation products in COVID-19 patients, convalescents, and healthy subjects, and to the determine the diagnostic applicability of these parameters in COVID-19 patients.
Materials and Methods: The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects who were selected for the research based on age and sex. The study was conducted between 20 February 2021 and 20 November 2021 in Białystok, Poland. The antioxidant barrier, redox status, and oxidative damage products were assessed in serum/plasma samples with the use of colorimetric and spectrophotometric assays.
Results: Glutathione reductase (GR) activity was higher, whereas total antioxidant capacity (TAC) was lower in COVID-19 patients than in convalescents (p<0.0001) and the control group (p<0.0001). The concentrations of advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA) were higher in COVID-19 patients (p<0.0001) and convalescents (p<0.0001) than in the control group. AGEs were the most effective diagnostic biomarker for differentiating COVID-19 patients from the control group (AUC=0.9971) and convalescents from the control group (AUC=1.000).
Conclusion: An infection with the SARS-CoV-2 disrupts the redox balance and increases protein oxidation and lipid peroxidation. AGEs fulfill the criteria for a potential diagnostic biomarker in COVID-19 patients and convalescents.

Keywords:  COVID-19; SARS CoV-2 virus; antioxidants; oxidative stress; redox biomarkers

DOI:  https://doi.org/10.2147/JIR.S456849
Am J Med Sci. 2024 May 01. pii: S0002-9629(24)01213-8. [Epub ahead of print]

Metformin as adjuvant treatment in hepatitis C virus infections and associated complications.

Dylan Landis, Alex Sutter, Sachi Khemka, Busara Songtanin, Jacob Nichols, Kenneth Nugent.

  Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.

Keywords:  Hepatitis C virus; hepatitis; hepatocellular carcinoma; insulin resistance; metformin

DOI:  https://doi.org/10.1016/j.amjms.2024.04.019
Sci Rep. 2024 May 03. 14(1): 10238

The severity of COVID-19 upon hospital admission is associated with plasma omega-3 fatty acids.

Ligia P Fernandes, Igor H Murai, Alan L Fernandes, Lucas P Sales, Marcelo M Rogero, Bruno Gualano, Lúcia P Barroso, Ginger L Milne, Rosa M R Pereira, Inar A Castro.

  Fatty acids are precursors of inflammatory oxylipins. In the context of COVID-19, an excessive production of pro-inflammatory cytokines is associated with disease severity. The objective was to investigate whether the baseline omega 3/omega 6 fatty acids ratio and the oxylipins were associated with inflammation and oxidative stress in unvaccinated patients with COVID-19, classified according to the severity of the disease during hospitalization. This Prospective population-based cohort study included 180 hospitalized patients with COVID-19. The patients were classified into five groups according to the severity of their disease. Group 1 was the least severe and Group 5 was the most severe. Three specific types of fatty acids-eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)-as well as their enzymatic and non-enzymatic oxylipins were determined using chromatography coupled mass spectrometry. There was no difference in the ratio of omega-3 to omega-6 fatty acids between the groups (p = 0.276). However, the EPA/AA ratio was lower in Group 4 compared to Group 1 (p = 0.015). This finding was associated with an increase in both C-Reactive Protein (p < 0.001) and Interleukin-6 (p = 0.002). Furthermore, the concentration of F2-Isoprostanes was higher in Group 4 than in Group 1 (p = 0.009), while no significant changes were observed for other oxylipins among groups. Multivariate analysis did not present any standard of biomarkers, suggesting the high complexity of factors involved in the disease severity. Our hypothesis was confirmed in terms of EPA/AA ratio. A higher EPA/AA ratio upon hospital admission was found to be associated with lower concentration of C-Reactive Protein and Interleukin-6, leading to a better prognosis of hospitalized SARS-CoV-2 patients. Importantly, this beneficial outcome was achieved without any form of supplementation. The trial also provides important information that can be further applied to reduce the severity of infections associated with an uncontrolled synthesis of pro-inflammatory cytokines.Trial registration: https://clinicaltrials.gov/study/NCT04449718 -01/06/2020. ClinicalTrials.gov Identifier: NCT04449718.

Keywords:  COVID; Cytokine; Eicosapentaenoic; Fatty acids; Oxylpins

DOI:  https://doi.org/10.1038/s41598-024-60815-y