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.

Local type I IFN production is critical to limit viral spread within the CNS [65] whereas CNS deficiency in IFNAR increases the susceptibility of lethal virus infection [13, 17, 18, [66] [67] [68] . Using the TBEV model LGTV, we have previously demonstrated the impact of locally produced type I IFN response within the CNS [11] ; Fig. 6 Gene set enrichment analysis of transcriptomic changes. The schematic histogram shows a typical expression profile of the transcriptomic changes after treatment (y-axis = fold changes; x-axis = one vertical line (stick) represents one transcript; red, up; blue, down). mRNA transcripts (sticks) and gene sets (names) that are high in IFNAR −/− astrocytes, IFNαB/D and supernatant-treated WT astrocytes, compared to WT astrocytes, are marked as red. Genes and gene sets that are downregulated or have a negative normalized enrichment score (NES), respectively, compared to WT astrocytes are blue. pval nominal p value, adj.pval Benjamini-Hochberg adjusted p value. An adj.pval <0.05 is regarded significant however, it is not clear which cells produce type I IFN in the CNS during TBEV infection. Astrocytes have been shown to produce an array of innate inflammatory mediators upon stimulation using polyinosinic:polycytidylic acid, lipopolysaccharide, and toll-like receptor (TLR)-7 and TLR-9 agonists [69] [70] [71] [72] . Studies have shown that astrocytes are the main producers of type I IFN within the CNS during VSV and La Cross virus infections [18, 23] . Recent studies have shown that TBEV and WNV can infect astrocytes in vitro but fail to spread from cell to cell. However, what prevents viral spread in astrocytes is not known [34, 36] . Our recent results show that neurons are the main target of LGTV infection; however, a small number of astrocytes also become infected. During infection, astrocytes show an activated phenotype in vivo and more cells become infected after LGTV infection in IPS-1-deficient mice [33] , indicating that type I IFN response might contribute to the restricted growth of virus in astrocytes.