bims-mevinf 2024-08-18 papers

Int Immunopharmacol. 2024 Aug 10. pii: S1567-5769(24)01433-4. [Epub ahead of print]140 112912

Impact of SARS-CoV-2 infection on immune cell cuproptosis in patients with lung adenocarcinoma via glutamine regulation.

Dan Wang, Xijin Deng, Shanshan Li, Si Ri Gu Leng Sana.

OBJECTIVE: Lung adenocarcinoma (LA), the most prevalent type of lung cancer, is associated with a high mortality rate, especially among patients with cancer previously infected with coronavirus disease (COVID-19). Therefore, this study aimed to explore the mechanisms by which COVID-19 exacerbates LA progression in a clinical setting.
METHODS: The experiment involved collecting serum samples from three groups: a healthy control group (Con, n = 20), a lung adenocarcinoma group (LA, n = 30), and a group of lung adenocarcinoma patients with first-time COVID-19 infection (C-LA, n = 58). Metabolites were analyzed using liquid chromatography-mass spectrometry, and differentially expressed metabolites were identified through bioinformatics analysis. The concentrations of glutathione (GSH), reactive oxygen species (ROS), and copper ions (Cu2+) in the serum of patients in the Con and C-LA groups were measured. Mitochondrial morphological changes in monocytes and lymphocytes were observed using electron microscopy.
RESULTS: Metabolomic analysis revealed 142 distinct metabolites, among which glutamine (Gln) expression was significantly decreased in the C-LA group. Compared to the Con group, the C-LA group showed a significant decrease in GSH and a notable increase in ROS and Cu2+. Further research revealed that the mitochondria of monocytes and lymphocytes in the C-LA group exhibited corresponding alterations indicative of cuproptosis.
CONCLUSIONS: SARS-CoV-2 infection may reduce Gln levels, leading to reduced GSH levels, copper overload, and increased death of immune cells, which may further exacerbate rapid tumor development. Thus, glutamine regulation plays an important role in LA progression in patients with COVID-19 and represents a potential therapeutic target.

Keywords: COVID-19; Cuproptosis; Glutamine; Lung adenocarcinoma; Mitochondria

DOI: https://doi.org/10.1016/j.intimp.2024.112912

Virology. 2024 Aug 05. pii: S0042-6822(24)00211-3. [Epub ahead of print]599 110190

Proviral and antiviral roles of phosphofructokinase family of glycolytic enzymes in TBSV replication.

Yuyan Liu, Wenwu Lin, Peter D Nagy.

Positive-strand RNA viruses build viral replication organelles (VROs) with the help of co-opted host factors. The biogenesis of the membranous VROs requires major metabolic changes in infected cells. Previous studies showed that tomato bushy stunt virus (TBSV) hijacks several glycolytic enzymes to produce ATP locally within VROs. In this work, we demonstrate that the yeast Pfk2p phosphofructokinase, which performs a rate-limiting and highly regulated step in glycolysis, interacts with the TBSV p33 replication protein. Deletion of PFK2 reduced TBSV replication in yeast, suggesting proviral role for Pfk2p. TBSV also co-opted two plant phosphofructokinases, which supported viral replication and ATP production within VROs, thus acting as proviral factors. Three other phosphofructokinases inhibited TBSV replication and they reduced ATP production within VROs, thus functioning as antiviral factors. Altogether, different phosphofructokinases have proviral or antiviral roles. This suggests on-going arms race between tombusviruses and their hosts to control glycolysis pathway in infected cells.

Keywords: ATP generation; Antiviral factor; Glycolysis; Host factor; Nicotiana benthamiana; Proviral factor; Replication; Tomato bushy stunt virus; Virus-host interaction; Yeast

DOI: https://doi.org/10.1016/j.virol.2024.110190

Poult Sci. 2024 Jul 30. pii: S0032-5791(24)00704-1. [Epub ahead of print]103(10): 104125

Effects of H9N2 avian influenza virus infection on metabolite content and gene expression in chick DF1 cells.

Yijia Zhang, Li Li, Xin Xin, Lifeng Chang, Haowei Luo, Wenna Qiao, Jun Xia, Jihui Ping, Juan Su.

After viral infection, the virus relies on the host cell's complex metabolic and biosynthetic machinery for replication. However, the impact of avian influenza virus (AIV) on metabolites and gene expression in poultry cells remains unclear. To investigate this, we infected chicken embryo fibroblasts DF1 cells with H9N2 AIV at an MOI of 3. Our aim was to explore how H9N2 AIV alters DF1 cells metabolic pathways to facilitate its replication. We employed metabolomics and transcriptomics techniques to analyze changes in metabolite content and gene expression. Metabolomics analysis revealed a significant increase in glutathione-related metabolites, including reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) upon H9N2 AIV infection in DF1 cells. Elisa results confirmed elevated levels of GSH, GSSG, and T-GSH consistent with metabolomics findings, noting a pronounced increase in GSSG compared to GSH. Transcriptomics showed significant alterations in genes involved in glutathione synthesis and metabolism post-H9N2 infection. However, adding the glutathione synthesis inhibitor BSO exogenously significantly promoted H9N2 replication in DF1 cells. This was accompanied by increased mRNA levels of pro-inflammatory cytokines (IL-1β, IFN-γ) and decreased mRNA levels of anti-inflammatory cytokines (TGF-β, IL-13). BSO also reduced catalase (CAT) gene expression and inhibited its activity, leading to higher reactive oxygen species (ROS) and malondialdehyde (MDA) level in DF1 cells. qPCR results indicated decreased mRNA levels of Nrf2, NQO1, and HO-1 with BSO, ultimately increasing oxidative stress in DF1 cells. Therefore, the above results indicated that H9N2 AIV infection in DF1 cells activated the glutathione metabolic pathway to enhance the cell's self-defense mechanism against H9N2 replication. However, when GSH synthesis is inhibited within the cells, it leads to an elevated oxidative stress level, thereby promoting H9N2 replication within the cells through Nrf2/HO-1 pathway. This study provides a theoretical basis for future rational utilization of the glutathione metabolic pathway to prevent viral replication.

Keywords: DF1 cell; GSH; H9N2; glutathione metabolism; oxidative stress

DOI: https://doi.org/10.1016/j.psj.2024.104125

Int J Biol Macromol. 2024 Aug 13. pii: S0141-8130(24)05443-6. [Epub ahead of print] 134638

SARS-CoV-2 uses Spike glycoprotein to control the host's anaerobic metabolism by inhibiting LDHB.

Vittoria Monaco, Ilaria Iacobucci, Luisa Canè, Irene Cipollone, Veronica Ferrucci, Pasqualino de Antonellis, Miriana Quaranta, Stefano Pascarella, Massimo Zollo, Maria Monti.

The SARS-CoV-2 pandemic, responsible for approximately 7 million deaths worldwide, highlights the urgent need to understand the molecular mechanisms of the virus in order to prevent future outbreaks. The Spike glycoprotein of SARS-CoV-2, which is critical for viral entry through its interaction with ACE2 and other host cell receptors, has been a focus of study. This research goes beyond receptor recognition to explore Spike's influence on cellular metabolism. AP-MS interactome analysis revealed an interaction between the Spike S1 domain and lactate dehydrogenase B (LDHB), which was further confirmed by co-immunoprecipitation and immunofluorescence, indicating colocalisation in cells expressing the S1 domain. The study showed that Spike inhibits the catalytic activity of LDHB, leading to increased lactate levels in HEK-293T cells overexpressing the S1 subunit. The hypothesised mechanism is that Spike deprives LDHB of NAD+, facilitating a metabolic switch from aerobic to anaerobic energy production during infection. The Spike-NAD+ interacting region was characterised and mainly involves the W436 within the RDB domain. This novel hypothesis suggests that the Spike protein may play a broader role in altering host cell metabolism, thereby contributing to the pathophysiology of viral infection.

Keywords: LDHB; SARS-CoV-2; Spike glycoprotein

DOI: https://doi.org/10.1016/j.ijbiomac.2024.134638

Virol J. 2024 Aug 12. 21(1): 185

Unveiling the intersection: ferroptosis in influenza virus infection.

Arash Letafati, Zahra Taghiabadi, Omid Salahi Ardekani, Simin Abbasi, Ali Qaraee Najafabadi, Negar Nayerain Jazi, Roben Soheili, Ramón Rodrigo, Jila Yavarian, Luciano Saso.

The influenza virus (IFV) imposes a considerable health and economic burden globally, requiring a comprehensive understanding of its pathogenic mechanisms. Ferroptosis, an iron-dependent lipid peroxidation cell death pathway, holds unique implications for the antioxidant defense system, with possible contributions to inflammation. This exploration focuses on the dynamic interplay between ferroptosis and the host defense against viruses, emphasizing the influence of IFV infections on the activation of the ferroptosis pathway. IFV causes different types of cell death, including apoptosis, necrosis, and ferroptosis. IFV-induced ferroptotic cell death is mediated by alterations in iron homeostasis, intensifying the accumulation of reactive oxygen species and promoting lipid peroxidation. A comprehensive investigation into the mechanism of ferroptosis in viral infections, specifically IFV, has great potential to identify therapeutic strategies. This understanding may pave the way for the development of drugs using ferroptosis inhibitors, presenting an effective approach to suppress viral infections.

Keywords: Cell death; Ferroptosis; Inflammation; Influenza virus; Lipid peroxidation; Oxidative stress

DOI: https://doi.org/10.1186/s12985-024-02462-3

Int J Mol Sci. 2024 Jul 31. pii: 8370. [Epub ahead of print]25(15):

Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients.

Mitsuru Tsuge, Eiki Ichihara, Kou Hasegawa, Kenichiro Kudo, Yasushi Tanimoto, Kazuhiro Nouso, Naohiro Oda, Sho Mitsumune, Goro Kimura, Haruto Yamada, Ichiro Takata, Toshiharu Mitsuhashi, Akihiko Taniguchi, Kohei Tsukahara, Toshiyuki Aokage, Hideharu Hagiya, Shinichi Toyooka, Hirokazu Tsukahara, Yoshinobu Maeda.

This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia.

Keywords: arginine; asymmetric dimethylarginine; citrulline; hydroperoxide; nitric oxide; novel coronavirus disease 2019; pneumonia; reactive oxygen species

DOI: https://doi.org/10.3390/ijms25158370