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

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-beta 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-beta was not detectable, while infected astrocytes showed high and microglia low IFN-beta 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-beta responses. Nevertheless, at later time points, moderate amounts of IFN-beta 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-beta responses of TBEV-infected WT astrocytes and blocked entirely IFN-beta responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-beta producers showing biphasic IFN-beta induction that initially depends on MAVS and later on MyD88/TRIF signaling.

Automated summary

In TBEV-infected mice, astrocytes are important producers of IFN-beta, showing biphasic induction that depends on MAVS initially and later on MyD88/TRIF signaling. Astrocytes play a crucial role in early anti-viral responses, while MAVS deficiency negatively affects this response, resulting in increased TBEV replication. Treatment with inhibiting peptides can reduce late IFN-beta responses in WT astrocytes and block entirely IFN-beta responses in MAVS-deficient astrocytes after TBEV exposure.