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Sequential MAVS and MyD88/TRIF signaling triggers anti‐viral responses of tick‐borne encephalitis virus‐infected murine astrocytes
Author(s) -
Ghita Luca,
Breitkopf Veronika,
Mulenge Felix,
Pavlou Andreas,
Gern Olivia Luise,
Durán Verónica,
Prajeeth Chittappen Kandiyil,
Kohls Moritz,
Jung Klaus,
Stangel Martin,
Steffen Imke,
Kalinke Ulrich
Publication year - 2021
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24923
Subject(s) - microglia , biology , trif , interferon , encephalitis , virology , flavivirus , virus , viral encephalitis , tick borne encephalitis virus , immunology , microbiology and biotechnology , innate immune system , immune system , inflammation , toll like receptor
Tick‐borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV‐infected mice, mitochondrial antiviral‐signaling protein (MAVS), the downstream adaptor of retinoic acid‐inducible gene‐I (RIG‐I)‐like receptor (RLR) signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To characterize the brain‐resident cell subset that produces protective IFN‐β in TBEV‐infected mice, we isolated neurons, astrocytes, and microglia from mice and exposed these cell types to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN‐β was not detectable, while infected astrocytes showed high and microglia low IFN‐β expression. Transcriptome analyses of astrocytes implied that MAVS signaling was needed early after TBEV infection. Accordingly, MAVS‐deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN‐β responses. Nevertheless, at later time points, moderate amounts of IFN‐β were detected in the SN of infected MAVS‐deficient astrocytes. Transcriptome analyses indicated that MAVS deficiency negatively affected the induction of early anti‐viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced only late IFN‐β responses of TBEV‐infected WT astrocytes and blocked entirely IFN‐β responses of infected MAVS‐deficient astrocytes. Thus, upon TBEV exposure of brain‐resident cells, astrocytes are important IFN‐β producers showing biphasic IFN‐β induction that initially depends on MAVS and later on MyD88/TRIF signaling.