bims-mevinf 2023-09-03 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–09–03
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

The glucose metabolic reprogramming in hepatitis B virus infection and hepatitis B virus associated diseases.
Hypoxia-inducible-factors differentially contribute to clinical disease and the control of viral replication during RSV infection.
Lipid metabolic reprogramming of hepatic CD4+ T cells during SIV infection.
NAD+-boosting compounds enhance nitric oxide production and prevent oxidative stress in endothelial cells exposed to plasma from patients with COVID-19.
Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states.
SCD1 inhibits HBV replication by regulating autophagy under high lipid conditions.
Transcriptomic analysis reveals the role of Glycolysis pathway in Litopenaeus vannamei during DIV1 infection.
Metformin in COVID-19: Is There a Role Beyond Glycemic Control?

J Gastroenterol Hepatol. 2023 Sep 01.

The glucose metabolic reprogramming in hepatitis B virus infection and hepatitis B virus associated diseases.

Hangle Wang, Jun Zhang.

  Hepatitis B virus (HBV) infection is closely related to viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. HBV infection can reprogram metabolism processes of the host cells including glucose metabolism. The aberrant glucose metabolism may aid in viral infection and immune escape and may contribute to liver associated pathology. In this review, we discussed the interplay between HBV infection and glucose metabolism, which may provide new insights into HBV infection and pathology, novel intervention targets for HBV-related diseases.

Keywords:  Cirrhosis; Glucose metabolism; Hepatitis B virus; Hepatocellular carcinoma; Immune escape

DOI:  https://doi.org/10.1111/jgh.16340
bioRxiv. 2023 Aug 17. pii: 2023.08.15.553422. [Epub ahead of print]

Hypoxia-inducible-factors differentially contribute to clinical disease and the control of viral replication during RSV infection.

Dorothea R Morris, Yue Qu, Yava L Jones-Hall, Teodora Ivanciuc, Tianshuang Liu, Roberto P Garofalo, Antonella Casola.

Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to stabilize this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previous in vitro studies, we demonstrate respiratory syncytial virus (RSV), a leading cause of respiratory illness, to stabilize HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of anti-HIF-1α (PX478) and anti-HIF-2α (PT2385) in RSV-infected BALB/c mice. We found inhibition of HIF-1α to worsen clinical disease parameters, while simultaneously improving airway function. Additionally, anti-HIF-1α results in significantly reduced viral titer at early and peak time points of RSV replication, followed by a loss in viral clearance when given every day, but not every-other-day. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, and amelioration of interstitial pneumonia. Furthermore, anti-HIF-2α reduced early and peak lung viral replication, with no impaired viral clearance. Analysis of lung cells found significant modification in the T cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. These data underscore the complex role of HIFs in RSV infection and highlight the need for careful therapeutic consideration.
Importance: The pharmacological use of HIF therapeutics has largely been investigated with various models of cancer, autoimmunity, and non-infectious lung damage. The safety and success of these compounds is emphasized by their use in several phase-4 clinical trials. Since the early 2000s, numerous studies have demonstrated the antiviral potential of HIF inhibitors in epithelial cell lines, however, there are no studies characterizing the therapeutic outcomes of suppressing HIF during a viral respiratory infection in a relevant animal model. With the growing interest in drug repositioning, our research emphasizes the importance of testing approved or abandoned therapeutics under the new conditions in a complex biological model encompassing both the epithelial and immune compartments. Moreover, the current study uncovers a novel role of HIFs in the pathogenesis of RSV disease. These data collectively demonstrate a key mechanism in immune regulation during RSV infection that can further therapeutic development.

DOI: https://doi.org/10.1101/2023.08.15.553422
Microbiol Spectr. 2023 Sep 01. e0168723

Lipid metabolic reprogramming of hepatic CD4+ T cells during SIV infection.

Julien A Clain, Steven Boutrais, Juliette Dewatines, Gina Racine, Henintsoa Rabezanahary, Arnaud Droit, Ouafa Zghidi-Abouzid, Jérôme Estaquier.

  While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.

Keywords:  AIDS; CCR5; CD4; PD-1; SIV; autophagy; cytotoxic; ferroptosis; granzyme; lipid; liver; metabolism; viral reservoir

DOI:  https://doi.org/10.1128/spectrum.01687-23
Nitric Oxide. 2023 Aug 30. pii: S1089-8603(23)00072-1. [Epub ahead of print]

NAD+-boosting compounds enhance nitric oxide production and prevent oxidative stress in endothelial cells exposed to plasma from patients with COVID-19.

Kaitlin A Freeberg, Katelyn R Ludwig, Michel Chonchol, Douglas R Seals, Matthew J Rossman.

  SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), induces vascular endothelial dysfunction, but the mechanisms are unknown. We tested the hypothesis that the "circulating milieu" (plasma) of patients with COVID-19 would cause endothelial cell dysfunction (characterized by lower nitric oxide (NO) production), which would be linked to greater reactive oxygen species (ROS) bioactivity and depletion of the critical metabolic co-substrate, nicotinamide adenine dinucleotide (NAD+). We also investigated if treatment with NAD+-boosting compounds would prevent COVID-19-induced reductions in endothelial cell NO bioavailability and oxidative stress. Human aortic endothelial cells (HAECs) were exposed to plasma from men and women (age 18-85 years) who were hospitalized and tested positive (n = 34; 20 M) or negative (n = 13; 10 M) for COVID-19. HAECs exposed to plasma from patients with COVID-19 also were co-incubated with NAD+ precursors nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). Acetylcholine-stimulated NO production was 27% lower and ROS bioactivity was 54% higher in HAECs exposed to plasma from patients with COVID-19 (both p < 0.001 vs. control); these responses were independent of age and sex. NAD+ concentrations were 30% lower in HAECs exposed to plasma from patients with COVID-19 (p = 0.001 vs. control). Co-incubation with NR abolished COVID-19-induced reductions in NO production and oxidative stress (both p > 0.05 vs. control). Co-treatment with NMN produced similar results. Our findings suggest the circulating milieu of patients with COVID-19 promotes endothelial cell dysfunction, characterized by lower NO bioavailability, greater ROS bioactivity, and NAD+ depletion. Supplementation with NAD+ precursors may exert a protective effect against COVID-19-evoked endothelial cell dysfunction and oxidative stress.

Keywords:  Nitric oxide; Reactive oxygen species; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.niox.2023.08.003
Cancer Metab. 2023 Aug 31. 11(1): 13

Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states.

Sara R Privatt, Camila Pereira Braga, Alicia Johnson, Salum J Lidenge, Luke Berry, John R Ngowi, Owen Ngalamika, Andrew G Chapple, Julius Mwaiselage, Charles Wood, John T West, Jiri Adamec.

   BACKGROUND: Kaposi sarcoma (KS) is a neoplastic disease etiologically associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV). KS manifests primarily as cutaneous lesions in individuals due to either age (classical KS), HIV infection (epidemic KS), or tissue rejection preventatives in transplantation (iatrogenic KS) but can also occur in individuals, predominantly in sub-Saharan Africa (SSA), lacking any obvious immune suppression (endemic KS). The high endemicity of KSHV and human immunodeficiency virus-1 (HIV) co-infection in Africa results in KS being one of the top 5 cancers there. As with most viral cancers, infection with KSHV alone is insufficient to induce tumorigenesis. Indeed, KSHV infection of primary human endothelial cell cultures, even at high levels, is rarely associated with long-term culture, transformation, or growth deregulation, yet infection in vivo is sustained for life. Investigations of immune mediators that distinguish KSHV infection, KSHV/HIV co-infection, and symptomatic KS disease have yet to reveal consistent correlates of protection against or progression to KS. In addition to viral infection, it is plausible that pathogenesis also requires an immunological and metabolic environment permissive to the abnormal endothelial cell growth evident in KS tumors. In this study, we explored whether plasma metabolomes could differentiate asymptomatic KSHV-infected individuals with or without HIV co-infection and symptomatic KS from each other.
METHODS: To investigate how metabolic changes may correlate with co-infections and tumorigenesis, plasma samples derived from KSHV seropositive sub-Saharan African subjects in three groups, (A) asymptomatic (lacking neoplastic disease) with KSHV infection only, (B) asymptomatic co-infected with KSHV and HIV, and (C) symptomatic with clinically diagnosed KS, were subjected to analysis of lipid and polar metabolite profiles RESULTS: Polar and nonpolar plasma metabolic differentials were evident in both comparisons. Integration of the metabolic findings with our previously reported KS transcriptomics data suggests dysregulation of amino acid/urea cycle and purine metabolic pathways, in concert with viral infection in KS disease progression.
CONCLUSIONS: This study is, to our knowledge, the first to report human plasma metabolic differentials between in vivo KSHV infection and co-infection with HIV, as well as differentials between co-infection and epidemic KS.

Keywords:  Biomarkers; HIV; KSHV; Kaposi sarcoma; Metabolite profiling; Metabolomics

DOI:  https://doi.org/10.1186/s40170-023-00316-0
Virus Genes. 2023 Aug 29.

SCD1 inhibits HBV replication by regulating autophagy under high lipid conditions.

Xuan Du, Xiaoyi Shi, Mei Han, Xiaoyun Gao, Chuang Wang, Chunmeng Jiang, Chunwen Pu.

  Chronic hepatitis B virus (HBV) infection remains a significant public health concern worldwide. Several metabolic processes regulate HBV DNA replication, including autophagy and lipid metabolism. In this study, we clarified the effect of lipids on HBV replication and elucidated possible mechanisms. We discovered that lipid metabolic gene expression levels were negatively correlated with the HBV DNA in plasma. Our data showed that fatty acid stimulation significantly reduced HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) levels in HepG2.2.15 cells, which are human hepatoma cell cultures transfected with HBV DNA. The Stearoyl coenzyme A desaturase 1 (SCD1)-autophagy pathway has also been implicated in inhibiting HBV replication by fatty acids stimulation. SCD1 knockdown deregulates the inhibitory effect of fatty acids on HBV by enhancing autophagy. When 3 methyladenine (3MA) was added, the inhibitory effects of specific autophagy inhibitors eliminated the positive effects of SCD1 knockdown on HBV replication. Our results indicate that SCD1 participates in the regulation of inhibition of HBV replication by fatty acids stimulation through regulating autophagy.

Keywords:  Autophagy; HBV; Lipid metabolism; SCD1

DOI:  https://doi.org/10.1007/s11262-023-02028-5
Fish Shellfish Immunol. 2023 Aug 26. pii: S1050-4648(23)00522-3. [Epub ahead of print]141 109036

Transcriptomic analysis reveals the role of Glycolysis pathway in Litopenaeus vannamei during DIV1 infection.

Xuzheng Liao, Sihong Liu, Shihan Chen, Xinxin Shan, Jianguo He, Chaozheng Li.

  In recent years, shrimp farming has experienced significant losses due to the emergence of DIV1 (Decapod iridescent virus 1), an infectious virus with a high fatality rate among shrimp. In this study, we conducted transcriptomic analyses on shrimp Litopenaeus vannamei hemocytes following DIV1 infection and focused on the function of genes in the Glycolysis pathway during DIV1 infection. A total of 2197 differentially expressed genes (DEGs) were identified, comprising 1506 up-regulated genes and 691 down-regulated genes. These genes were primarily associated with Phagosome, ECM-Receptor Interaction, Drug Metabolism-Other Enzymes, and the AGE-RAGE signaling pathway in diabetic complications. KEGG pathway enrichment analysis of the DEGs revealed a noteworthy correlation with metabolic pathways, with a specific focus on glucose metabolism. Specifically, the Glycolysis/Gluconeogenesis pathway exhibited significant upregulation following DIV1 infection. In line with this, we observed an augmented accumulation of glycolytic-related metabolites in the hemolymph following DIV1 challenge along with upregulation of the relative mRNA expression of several glycolytic-related genes. Moreover, we found that the inhibition of lactate dehydrogenase (LDH) activity through RNAi or the use of an inhibitor resulted in reduced lactate production, effectively safeguarding shrimp from DIV1 infection. These findings not only provide a comprehensive dataset for further investigation into DIV1 pathogenesis but also offer valuable insights into the immunometabolism mechanisms that govern shrimp responses to DIV1 infection.

Keywords:  Decapod iridescent virus 1; Glycolysis; Litopenaeus vannamei; Transcriptomic analysis

DOI:  https://doi.org/10.1016/j.fsi.2023.109036
Int J Endocrinol Metab. 2023 Apr;21(2): e132965

Metformin in COVID-19: Is There a Role Beyond Glycemic Control?

Lakshmi Nagendra, Saptarshi Bhattacharya, Sanjay Kalra, Nitin Kapoor.

   Context: The coronavirus disease 2019 (COVID-19) pandemic is still a cause of worldwide health concern. Diabetes and its associated comorbidities are risk factors for mortality and morbidity in COVID-19. Selecting the right antidiabetic drug to achieve optimal glycemic control might mitigate some of the negative impacts of diabetes. Metformin continues to be the most widely administered antidiabetic agent. There is evidence of its beneficial outcome in COVID-19 independent of its glucose-lowering effect.
Evidence Acquisition: A thorough literature search was conducted in PubMed, Google Scholar, Scopus, and Web of Science to identify studies investigating metformin in COVID-19.
Results: Several overlapping mechanisms have been proposed to explain its antiviral properties. It could bring about conformational changes in the angiotensin-converting enzyme-2 receptor and decrease viral entry. The effects on the mammalian target of the rapamycin pathway and cellular pH have been proposed to reduce viral protein synthesis and replication. The immunomodulatory effects of metformin might counter the detrimental effects of hyperinflammation associated with COVID-19.
Conclusions: These findings call for broader metformin usage to manage hyperglycemia in COVID-19.

Keywords:  ACE-2 Receptor; Antidiabetic Agents; COVID-19; Metformin

DOI:  https://doi.org/10.5812/ijem-132965