Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

Lindqvist, Richard; Mundt, Filip; Gilthorpe, Jonathan D.; Wölfel, Silke; Gekara, Nelson O.; Kröger, Andrea; Överby, Anna K.

While neurons are the main target of neurotropic flaviviruses, other cell types might also become infected and contribute to the resolution of infection [20] . Previous studies have shown that the IFN response and ISG expression in neurons restrict neurotropic flavivirus infection in neurons [19, 21] ; however, not much is known about the role of the IFN response in astrocytes during neurotropic flavivirus infection. Recent studies have shown that astrocytes are important IFN-producing cells in various neurotropic viral infections [18, 22, 23] . Astrocytes are one of the most abundant cell types in the brain and mediate diverse supportive functions including ion homeostasis [24, 25] , uptake of glutamate [26] , free radical scavenging [27] , and immune regulation [28] . In TBEV infection, autopsy studies have revealed astrogliosis in post mortem human brains [20, 29] , which has been observed for WNV and JEV as well [30, 31] . Indeed, astrocytes have been found to be a site of these infections [32] . However, only a few astrocytes were found to be infected in LGTV-infected mice [33] . They resist infection in an interferon-beta promoter stimulator 1 (IPS-1)-dependent manner and show an activated phenotype, indicating their involvement in LGTV clearance. Both rat and human astrocytes have been shown to be infected in vitro with TBEV; however, the number of infected cells never exceeded 20 %, and the infection did not affect astrocyte viability [34, 35] . Similar findings have also been observed for other neurotropic flaviviruses [36] [37] [38] [39] . Therefore, we set out to investigate how the type I IFN system in primary mouse astrocytes contributes to cell survival and restriction of neurotropic flavivirus growth.