bims-mevinf 2023-02-26 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–02–26
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact.
Potential Role of Superoxide Dismutase 3 (SOD3) in Resistance to Influenza A Virus Infection.
Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19.
Functional polyamine metabolic enzymes and pathways encoded by the virosphere.
After virus exposure, early bystander naïve CD8 T cell activation relies on NAD+ salvage metabolism.
Genetic diversity of virus auxiliary metabolism genes associated with phosphorus metabolism in Napahai plateau wetland.
Vitisin B inhibits influenza A virus replication by multi-targeting neuraminidase and virus-induced oxidative stress.
When AHR signaling pathways meet viral infections.

Biomedicines. 2023 Jan 19. pii: 271. [Epub ahead of print]11(2):

Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact.

Wesal Elgretli, Tianyan Chen, Nadine Kronfli, Giada Sebastiani.

  Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.

Keywords:  atherosclerosis; cholesterol; hepatitis C; lipid metabolism; steatosis

DOI:  https://doi.org/10.3390/biomedicines11020271
Antioxidants (Basel). 2023 Feb 02. pii: 354. [Epub ahead of print]12(2):

Potential Role of Superoxide Dismutase 3 (SOD3) in Resistance to Influenza A Virus Infection.

Feimin Chen, Liurong Chen, Jinlong Liang, Zhixuan Chen, Chunyu Zhang, Zhengyin Zhang, Jie Yang.

  Influenza A virus infection induces the production of excessive reactive oxygen species (ROS). Overproduction of ROS can overwhelm the antioxidant defense system, leading to increasing intensive oxidative stress. However, antioxidant defense against oxidative damage induced by influenza A virus infection, and in particular the significance of the SOD3 response in the pathogenesis of influenza virus infection, has not been well characterized. Here, we investigated the potential role of SOD3 in resistance to influenza A virus infection. In this study, SOD3, as an important antioxidant enzyme, was shown to be highly elevated in A549 cells following influenza A virus infection. Furthermore, inhibition of SOD3 impacted viral replication and virulence. We found that SOD3 disrupts IAV replication by impairing the synthesis of vRNA, whereas it did not affect viral ribonucleoprotein nuclear export. In addition, overexpression of SOD3 greatly reduced the levels of ROS caused by influenza A virus infection, regulated the inflammatory response to virus infection by inhibiting the phosphorylation of p65 of the NF-κB signaling pathway, and inhibited virus-induced apoptosis to a certain extent. Taken together, these findings indicate that SOD3 is actively involved in influenza A virus replication. Pharmacological modulation or targeting of SOD3 may pave the way for a novel therapeutic approach to combating influenza A virus infection.

Keywords:  ROS; SOD3; inflammatory response; influenza A virus; replication

DOI:  https://doi.org/10.3390/antiox12020354
Sci Immunol. 2023 Feb 23. eadf0348

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19.

Bibo Zhu, Xiaoqin Wei, Harish Narasimhan, Wei Qian, Ruixuan Zhang, In Su Cheon, Yue Wu, Chaofan Li, Russell G Jones, Mark H Kaplan, Robert A Vassallo, Thomas J Braciale, Lindsay Somerville, Jerry R Colca, Akhilesh Pandey, Patrick E H Jackson, Barbara J Mann, Connie M Krawczyk, Jeffrey M Sturek, Jie Sun.

The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

DOI: https://doi.org/10.1126/sciimmunol.adf0348
Proc Natl Acad Sci U S A. 2023 Feb 28. 120(9): e2214165120

Functional polyamine metabolic enzymes and pathways encoded by the virosphere.

Bin Li, Jue Liang, Hamid R Baniasadi, Margaret A Phillips, Anthony J Michael.

  Viruses produce more viruses by manipulating the metabolic and replication systems of their host cells. Many have acquired metabolic genes from ancestral hosts and use the encoded enzymes to subvert host metabolism. The polyamine spermidine is required for bacteriophage and eukaryotic virus replication, and herein, we have identified and functionally characterized diverse phage- and virus-encoded polyamine metabolic enzymes and pathways. These include pyridoxal 5'-phosphate (PLP)-dependent ornithine decarboxylase (ODC), pyruvoyl-dependent ODC and arginine decarboxylase (ADC), arginase, S-adenosylmethionine decarboxylase (AdoMetDC/speD), spermidine synthase, homospermidine synthase, spermidine N-acetyltransferase, and N-acetylspermidine amidohydrolase. We identified homologs of the spermidine-modified translation factor eIF5a encoded by giant viruses of the Imitervirales. Although AdoMetDC/speD is prevalent among marine phages, some homologs have lost AdoMetDC activity and have evolved into pyruvoyl-dependent ADC or ODC. The pelagiphages that encode the pyruvoyl-dependent ADCs infect the abundant ocean bacterium Candidatus Pelagibacter ubique, which we have found encodes a PLP-dependent ODC homolog that has evolved into an ADC, indicating that infected cells would contain both PLP- and pyruvoyl-dependent ADCs. Complete or partial spermidine or homospermidine biosynthetic pathways are found encoded in the giant viruses of the Algavirales and Imitervirales, and in addition, some viruses of the Imitervirales can release spermidine from the inactive N-acetylspermidine. In contrast, diverse phages encode spermidine N-acetyltransferase that can sequester spermidine into its inactive N-acetyl form. Together, the virome-encoded enzymes and pathways for biosynthesis and release or biochemical sequestration of spermidine or its structural analog homospermidine consolidate and expand evidence supporting an important and global role of spermidine in virus biology.

Keywords:  bacteriophage; polyamine; putrescine; spermidine; virus

DOI:  https://doi.org/10.1073/pnas.2214165120
Front Immunol. 2022 ;13 1047661

After virus exposure, early bystander naïve CD8 T cell activation relies on NAD+ salvage metabolism.

Namit Holay, Barry E Kennedy, J Patrick Murphy, Prathyusha Konda, Michael Giacomantonio, Tatjana Brauer-Chapin, Joao A Paulo, Vishnupriyan Kumar, Youra Kim, Mariam Elaghil, Gary Sisson, Derek Clements, Christopher Richardson, Steven P Gygi, Shashi Gujar.

  CD8 T cells play a central role in antiviral immunity. Type I interferons are among the earliest responders after virus exposure and can cause extensive reprogramming and antigen-independent bystander activation of CD8 T cells. Although bystander activation of pre-existing memory CD8 T cells is known to play an important role in host defense and immunopathology, its impact on naïve CD8 T cells remains underappreciated. Here we report that exposure to reovirus, both in vitro or in vivo, promotes bystander activation of naïve CD8 T cells within 24 hours and that this distinct subtype of CD8 T cell displays an innate, antiviral, type I interferon sensitized signature. The induction of bystander naïve CD8 T cells is STAT1 dependent and regulated through nicotinamide phosphoribosyl transferase (NAMPT)-mediated enzymatic actions within NAD+ salvage metabolic biosynthesis. These findings identify a novel aspect of CD8 T cell activation following virus infection with implications for human health and physiology.

Keywords:  CD8 T cells; NAD+ salvage metabolism; antiviral immunity; bystander activation; immunometabolism; metabolic reprogramming; naïve CD8 T cells; type I interferons

DOI:  https://doi.org/10.3389/fimmu.2022.1047661
Sci Rep. 2023 Feb 24. 13(1): 3250

Genetic diversity of virus auxiliary metabolism genes associated with phosphorus metabolism in Napahai plateau wetland.

Hang Yu, Lingling Xiong, Yanmei Li, Yunlin Wei, Qi Zhang, Haiyan Li, Wei Chen, Xiuling Ji.

Viruses play important roles in ecosystems by interfering with the central metabolic pathways of the host during infection via the expression of auxiliary metabolic genes (AMGs), altering the productivity of ecosystems and thus affecting geochemical cycling. In this study, the genetic diversity of phosphorus metabolism AMGs phoH, phoU and pstS was investigated by phylogenetic analysis, PCoA analysis, and alpha diversity analysis based on metagenomic data. It was found that the majority of the sequences were unique to Napahai plateau wetland. It was shown that the genetic diversity of phoH, phoU and pstS genes was independent of both habitats and host origins. In addition, the metabolic pathway of AMGs associated with the phosphorus cycling was identified based on metagenomic data. When phosphorus is deficient, virus utilizes AMGs to affect the metabolic pathway, contributing to higher phosphorus levels in the host and facilitating virus survival, replication, and propagation in the host cell.

DOI: https://doi.org/10.1038/s41598-023-28488-1
Acta Pharm Sin B. 2023 Jan;13(1): 174-191

Vitisin B inhibits influenza A virus replication by multi-targeting neuraminidase and virus-induced oxidative stress.

Eun-Bin Kwon, Wei Li, Young Soo Kim, Buyun Kim, Hwan-Suck Chung, Younghoon Go, Hyun-Jeong Ko, Jae-Hyoung Song, Young Ho Kim, Chun Whan Choi, Jang-Gi Choi.

  The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.

Keywords:  G6PD; Influenza; Multi-targeting; NF-κB; Neuraminidase; Nrf2; Reactive oxygen species; Vitis vinifera L.; Vitisin B

DOI:  https://doi.org/10.1016/j.apsb.2022.07.001
Cell Commun Signal. 2023 Feb 24. 21(1): 42

When AHR signaling pathways meet viral infections.

Jieke Hu, Yuan Ding, Wen Liu, Shuzhen Liu.

  Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional factor widely expressed among immune, epithelial, endothelial and stromal cells in barrier tissues. It can be activated by small molecules provided by pollutants, microorganisms, food, and metabolism. It has been demonstrated that AHR plays an important role in modulating the response to many microbial pathogens, and the abnormal expression of AHR signaling pathways may disrupt endocrine, cause immunotoxicity, and even lead to the occurrence of cancer. Most humans are infected with at least one known human cancer virus. While the initial infection with these viruses does not cause major disease, the metabolic activity of infected cells changes, thus affecting the activation of oncogenic signaling pathways. In the past few years, lots of studies have shown that viral infections can affect disease progression by regulating the transmission of multiple signaling pathways. This review aims to discuss the potential effects of virus infections on AHR signaling pathways so that we may find a new strategy to minimize the adverse effects of the AHR pathway on diseases. Video Abstract.

Keywords:  Aryl hydrocarbon receptor; Signaling pathway; Virus infections

DOI:  https://doi.org/10.1186/s12964-023-01058-8