1. Borna disease virus 1 induces ferroptosis, contributing to lethal encephalitis.
- Author
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Tan Q, Yang H, He Y, Shen X, Sun L, Du X, Lin G, Zhou N, Wang N, Zhou Q, Liu D, Xu X, Zhao L, and Xie P
- Subjects
- Animals, Rats, Humans, Reactive Oxygen Species metabolism, Signal Transduction, Amino Acid Transport System y+ metabolism, Amino Acid Transport System y+ genetics, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 genetics, Microglia virology, Microglia metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Heme Oxygenase-1 metabolism, Heme Oxygenase-1 genetics, Cell Line, Encephalitis virology, Encephalitis pathology, Cells, Cultured, Ferroptosis, Borna disease virus physiology, Rats, Sprague-Dawley, Neurons virology, Neurons pathology, Lipid Peroxidation, NF-E2-Related Factor 2 metabolism, NF-E2-Related Factor 2 genetics, Borna Disease virology, Borna Disease metabolism
- Abstract
Borna disease virus 1 (BoDV-1) is a neurotropic RNA virus that has been linked to fatal BoDV-1 encephalitis (BVE) in humans. Ferroptosis represents a newly recognized kind of programmed cell death that marked by iron overload and lipid peroxidation. Various viral infections are closely related to ferroptosis. However, the link between BoDV-1 infection and ferroptosis, as well as its role in BVE pathogenesis, remains inadequately understood. Herein, we used primary rat cortical neurons, human microglial HMC3 cells, and Sprague‒Dawley rats as models. BoDV-1 infection induced ferroptosis, as ferroptosis characteristics were detected (iron overload, reactive oxygen species buildup, decreased antioxidant capacity, lipid peroxidation, and mitochondrial damage). Analysis via qRT-PCR and Western blot demonstrated that BoDV-1-induced ferroptosis was mediated through Nrf2/HO-1/SLC7a11/GPX4 antioxidant pathway suppression. Nrf2 downregulation was due to BoDV-1 infection promoting Nrf2 ubiquitination and degradation. Following BoDV-1-induced ferroptosis, the PTGS2/PGE2 signaling pathway was activated, and various intracellular lipid peroxidation products and damage-associated molecular patterns were released, contributing to BVE occurrence and progression. More importantly, inhibiting ferroptosis or the ubiquitin‒proteasome system effectively alleviated BVE. Collectively, these findings demonstrate the interaction between BoDV-1 infection and ferroptosis and reveal BoDV-1-induced ferroptosis as an underlying pathogenic mechanism of BVE., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
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