Journal Article

Hepatitis B virus e antigen induces atypical metabolism and differentially regulates programmed cell deaths of macrophages

Wang, Sean, Li, Yumei, Akbari, Omid, Hurrell, Benjamin P., Wu, Christine, Lee, Jiyoung, Ou, Jing-hsiung James, Lim, Juhyeon, Ning, Qiqi, Eoh, Hyungjin

2024

Overview

Macrophages can undergo M1-like proinflammatory polarization with low oxidative phosphorylation (OXPHOS) and high glycolytic activities or M2-like anti-inflammatory polarization with the opposite metabolic activities. Here we show that M1-like macrophages induced by hepatitis B virus (HBV) display high OXPHOS and low glycolytic activities. This atypical metabolism induced by HBV attenuates the antiviral response of M1-like macrophages and is mediated by HBV e antigen (HBeAg), which induces death receptor 5 (DR5) via toll-like receptor 4 (TLR4) to induce death-associated protein 3 (DAP3). DAP3 then induces the expression of mitochondrial genes to promote OXPHOS. HBeAg also enhances the expression of glutaminases and increases the level of glutamate, which is converted to α-ketoglutarate, an important metabolic intermediate of the tricarboxylic acid cycle, to promote OXPHOS. The induction of DR5 by HBeAg leads to apoptosis of M1-like and M2-like macrophages, although HBeAg also induces pyroptosis of the former. These findings reveal novel activities of HBeAg, which can reprogram mitochondrial metabolism and trigger different programmed cell death responses of macrophages depending on their phenotypes to promote HBV persistence.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Antigens / Antiviral agents / Antiviral drugs / Apoptosis / Biochemistry / Biology and Life Sciences / Care and treatment / Cell death / Cytokines / Diagnosis / Dosage and administration / Gene expression / Genes / Genetic aspects / Genomes / Genotype & phenotype / Glutamate / Glycolysis / Health aspects / Hepatitis / Hepatitis associated antigen / Hepatitis B / Hepatitis B e antigen / Hepatitis B e Antigens - metabolism / Hepatitis B virus / Hepatitis B virus - genetics / Hepatitis C / Humans / Inflammation / Ketoglutaric acid / Liver cancer / Macrophages / Macrophages - metabolism / Medicine and Health Sciences / Metabolism / Mortality / Oxidative phosphorylation / Phenotypes / Phosphorylation / Physiological aspects / Polarization / Proteins / Pyroptosis / Quantitative analysis / Testing / TLR4 protein / Toll-like receptors / Tricarboxylic acid cycle / Tumor necrosis factor-TNF