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Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

Luca Ghita, Veronika Breitkopf, Felix Mulenge, Andreas Pavlou, Olivia Luise Gern, Verónica Durán, Chittappen Kandiyil Prajeeth, Moritz Kohls, Klaus Jung, Martin Stangel, Imke Steffen, Ulrich Kalinke
doi: https://doi.org/10.1101/2020.06.30.177485
Luca Ghita
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
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Veronika Breitkopf
2Institute of Physiological Chemistry and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany
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Felix Mulenge
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
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Andreas Pavlou
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
3Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
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Olivia Luise Gern
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
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Verónica Durán
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
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Chittappen Kandiyil Prajeeth
3Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
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Moritz Kohls
4Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559 Hanover, Germany
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Klaus Jung
4Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559 Hanover, Germany
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Martin Stangel
3Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
5Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
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Imke Steffen
2Institute of Physiological Chemistry and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany
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  • For correspondence: imke.steffen@tiho-hannover.de ulrich.kalinke@twincore.de
Ulrich Kalinke
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
5Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
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  • For correspondence: imke.steffen@tiho-hannover.de ulrich.kalinke@twincore.de
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Abstract

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-like receptor (RLR)-signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To identify the brain resident cell subset that produces protective IFN-β in TBEV infected mice, we isolated neurons, astrocytes and microglia and exposed these cells 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 very high and microglia low IFN-β production. 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. 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 late IFN-β responses of TBEV infected WT astrocytes and entirely blocked IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers that show biphasic IFN-β induction that initially depends on MAVS- and later on MyD88/TRIF-signaling.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 02, 2020.
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Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes
Luca Ghita, Veronika Breitkopf, Felix Mulenge, Andreas Pavlou, Olivia Luise Gern, Verónica Durán, Chittappen Kandiyil Prajeeth, Moritz Kohls, Klaus Jung, Martin Stangel, Imke Steffen, Ulrich Kalinke
bioRxiv 2020.06.30.177485; doi: https://doi.org/10.1101/2020.06.30.177485
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Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes
Luca Ghita, Veronika Breitkopf, Felix Mulenge, Andreas Pavlou, Olivia Luise Gern, Verónica Durán, Chittappen Kandiyil Prajeeth, Moritz Kohls, Klaus Jung, Martin Stangel, Imke Steffen, Ulrich Kalinke
bioRxiv 2020.06.30.177485; doi: https://doi.org/10.1101/2020.06.30.177485

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