bims-mevinf 2023-12-17 papers

J Pharm Biomed Anal. 2023 Dec 03. pii: S0731-7085(23)00669-6. [Epub ahead of print]239 115900

Metabolomic analysis identifies dysregulation of lipid metabolism in the immune clearance phase of chronic hepatitis B patients.

Xiangyang Ye, Xiongzhi He, Zhenting Hu, Fengfeng Zheng, Xiaogang Huang, Xuemei Xie, Feihua Chen, Hanbing Ou, Rongxian Qiu.

There is an accelerated progression of liver necroinflammation and fibrosis in the liver during the immune clearance (IC) phase of Chronic hepatitis B virus (HBV) infection, which are critical indicators of antiviral treatment for chronic hepatitis B (CHB) infection. This study applied serum metabolomics to identify the potential metabolite biomarkers for differential diagnosis between the CHB immune tolerance (IT) and Immune clearance (IC) phases. A liquid chromatography-mass spectrometry (LC-MS)-based approach was applied to evaluate and compared the serum metabolic profiles of 28 patients in IT phase and 33 patients in IC phase and appropriate statistical methods with MetaboAnalystR 2.0 R package to analyze those metabolites. The differential metabolites between IT and TC groups were classified and the top altered classification were lipids and lipid-like molecules and fatty acyls, clearly indicating that there were differences in the lipid metabolomic profile of HBV-infected patients with IT vs. IR phase. We identified the top 10 potential metabolite biomarkers for differential diagnosis between IT and IR. There were four lipid metabolites among them and the AUC of two of them, octadecadienoyl-sn-glycero-3-phosphocholine and 3-Cycloheptene-l-acetic acid, were 0.983 and 0.933. octadecadienoyl-sn-glycero-3-phosphocholine is Diacylglycerol (18:2n6/18:0) and 3-Cycloheptene-l-acetic acid is hydroxy fatty acids, both of which were associated with lipid metabolism. This study not only provides the potential metabolic biomarkers but also insight into the mechanism of CHB progression during IT clearance phase.

Keywords: Chronic hepatitis B; Lipid metabolism. immune clearance phase; Metabolite biomarkers; Metabolomics

DOI: https://doi.org/10.1016/j.jpba.2023.115900

JHEP Rep. 2024 Jan;6(1): 100936

SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH.

Luis Cano, Lise Desquilles, Gevorg Ghukasyan, Gaëlle Angenard, Clémence Landreau, Anne Corlu, Bruno Clément, Bruno Turlin, Eric Le Ferrec, Caroline Aninat, Julie Massart, Orlando Musso.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) results in steatosis, inflammation (steatohepatitis), and fibrosis. Patients with MASLD more likely develop liver injury in coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As viral RNA has been identified in liver tissues, we studied expression levels and cellular sources of the viral receptor angiotensin-converting enzyme 2 (ACE2) and coreceptors in MASLD and fibroinflammatory liver diseases.
Methods: We built a transcriptomic MASLD meta-dataset (N = 243) to study SARS-CoV-2 receptor expression and verified results in 161 additional cases of fibroinflammatory liver diseases. We assessed the fibroinflammatory microenvironment by deconvoluting immune cell populations. We studied the cellular sources of ACE2 by multiplex immunohistochemistry followed by high-resolution confocal microscopy (N = 9 fatty livers; N = 7 controls), meta-analysis of two single-cell RNA sequencing datasets (N = 5 cirrhotic livers; N = 14 normal livers), and bulk transcriptomics from 745 primary cell samples. In vitro, we tested ACE2 mRNA expression in primary human hepatocytes treated with inflammatory cytokines, bacterial lipopolysaccharides, or long-chain fatty acids.
Results: We detected ACE2 at the apical and basal poles of hepatocyte chords, in CLEC4M+ liver sinusoidal endothelial cells, the lumen of ABCC2+ bile canaliculi, HepPar-1+-TMPRSS2+ hepatocytes, cholangiocytes, and CD34+ capillary vessels. ACE2 steeply increased between 30 and 50 years of age; was related to liver fat area, inflammation, high immune reactivity, and fibrogenesis; and was upregulated in steatohepatitis. Although ACE2 mRNA was unmodified in alcoholic or viral hepatitis, it was upregulated in fibroinflammatory livers from overweight patients. In vitro, treatment of primary human hepatocytes with inflammatory cytokines alone downregulated but long chain fatty acids upregulated ACE2 mRNA expression.
Conclusions: Lipid overload in fatty liver disease leads to an increased availability of ACE2 receptors.
Impact and implications: COVID-19 can be a deadly disease in vulnerable individuals. Patients with fatty liver disease are at a higher risk of experiencing severe COVID-19 and liver injury. Recent studies have indicated that one of the reasons for this vulnerability is the presence of a key cell surface protein called ACE2, which serves as the main SARS-CoV-2 virus receptor. We describe the cellular sources of ACE2 in the liver. In patients with fatty liver disease, ACE2 levels increase with age, liver fat content, fibroinflammatory changes, enhanced positive immune checkpoint levels, and innate immune reactivity. Moreover, we show that long chain fatty acids can induce ACE2 expression in primary human hepatocytes. Understanding the cellular sources of ACE2 in the liver and the factors that influence its availability is crucial. This knowledge will guide further research and help protect potentially vulnerable patients through timely vaccination boosters, dietary adjustments, and improved hygiene practices.

Keywords: CLEC4M; DC-SIGNR; DPP4; MAFLD; Metabolic syndrome; Metabolism; NAFLD; NASH; Oleic acid; SARS-CoV-2; Stearic acid; TMPRSS2

DOI: https://doi.org/10.1016/j.jhepr.2023.100936

J Virol. 2023 Dec 13. e0167023

Lactate-lactylation-HSPA6 axis promotes PRRSV replication by impairing IFN-β production.

Yu Pang, Yanrong Zhou, Yucheng Wang, Liurong Fang, Shaobo Xiao.

IMPORTANCE: As a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-β production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.

Keywords: heat shock 70 kDa protein 6 (HSPA6); interferon; lactate; lactylation; porcine reproductive and respiratory syndrome virus

DOI: https://doi.org/10.1128/jvi.01670-23

Front Microbiol. 2023 ;14 1279655

The role of ferroptosis in virus infections.

Jing Wang, Junda Zhu, Shuning Ren, Zihui Zhang, Kang Niu, Hua Li, Wenxue Wu, Chen Peng.

Regulated cell death (RCD) is a strategy employed by host cells to defend invasions of pathogens, such as viruses and bacteria. Ferroptosis is a type of RCD characterized by excessive accumulation of iron and lipid peroxidation. While ferroptosis is primarily considered as a mechanism associated with tumorigenesis, emerging evidence begin to suggest that it may play essential role during virus infections. Recent studies illustrated that activation of ferroptosis could either induce or prohibit various types of RCDs to facilitate virus replication or evade host surveillance. More experimental evidence has demonstrated how viruses regulate ferroptosis to influence replication, transmission, and pathogenesis. This review summarizes ferroptosis-related metabolism, including iron metabolism, lipid peroxidation, and antioxidant metabolism. Furthermore, we discuss the interplay between viral infections and host ferroptosis process, with a focus on the mechanism of how viruses exploit ferroptosis for its own replication. Understanding how ferroptosis impacts virus infection can offer valuable insights into the development of effective therapeutic strategies to combat virus infections.

Keywords: ferroptosis; inhibitors and inducers; regulated cell death; viral infections; virus-host interaction

DOI: https://doi.org/10.3389/fmicb.2023.1279655

Antiviral Res. 2023 Dec 11. pii: S0166-3542(23)00258-9. [Epub ahead of print] 105780

The diverse roles of peroxisomes in the interplay between viruses and mammalian cells.

Hui Jiang, Venugopal Nair, Yingjie Sun, Chan Ding.

Peroxisomes are ubiquitous organelles found in eukaryotic cells that play a critical role in the oxidative metabolism of lipids and detoxification of reactive oxygen species (ROS). Recently, the role of peroxisomes in viral infections has been extensively studied. Although several studies have reported that peroxisomes promote viral replication, evidence indicates that viruses have also evolved diverse strategies to evade peroxisomal antiviral signals. In this review, we summarize the multiple roles of peroxisomes in the interplay between viruses and mammalian cells. Focus is given on the peroxisomal regulation of innate immune response, lipid metabolism, ROS production, and viral regulation of peroxisomal biosynthesis and degradation. Understanding the interactions between peroxisomes and viruses provides novel insights for the development of new antiviral strategies.

Keywords: Biosynthesis; Degradation; Function; Human and animal virus; Metabolism; Peroxisomes

DOI: https://doi.org/10.1016/j.antiviral.2023.105780