Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells.

BACKGROUND: Until the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear. METHODS: Here, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (Ifnar1-/-) and recombination-activating gene 1 (Rag1-/-). RESULTS: We show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset. CONCLUSIONS: Using intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.

Type I interferon-regulated gene expression and signaling in murine mixed glial cells lacking signal transducers and activators of transcription 1 or 2 or interferon regulatory factor 9.

Type I interferons (IFN-I) are critical in antimicrobial and antitumor defense. Although IFN-I signal via the interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2, and IRF9, IFN-I can mediate significant biological effects via ISGF3-independent pathways. For example, the absence of STAT1, STAT2, or IRF9 exacerbates neurological disease in transgenic mice with CNS production of IFN-I. Here we determined the role of IFN-I-driven, ISGF3-independent signaling in regulating global gene expression in STAT1-, STAT2-, or IRF9-deficient murine mixed glial cell cultures (MGCs). Compared with WT, the expression of IFN-α-stimulated genes (ISGs) was reduced in number and magnitude in MGCs that lacked STAT1, STAT2, or IRF9. There were significantly fewer ISGs in the absence of STAT1 or STAT2 versus in the absence of IRF9. The majority of ISGs regulated in the STAT1-, STAT2-, or IRF9-deficient MGCs individually were shared with WT. However, only a minor number of ISGs were common to WT and STAT1-, STAT2-, and IRF9-deficient MGCs. Whereas signal pathway activation in response to IFN-α was rapid and transient in WT MGCs, this was delayed and prolonged and correlated with increased numbers of ISGs expressed at 12 h versus 4 h of IFN-α exposure in all three IFN-I signaling-deficient MGCs. In conclusion, 1) IFN-I can mediate ISG expression in MGCs via ISGF3-independent signaling pathways but with reduced efficiency, with delayed and prolonged kinetics, and is more dependent on STAT1 and STAT2 than IRF9; and 2) signaling pathways not involving STAT1, STAT2, or IRF9 play a minor role only in mediating ISG expression in MGCs.