Type I Interferon Mitigates ZIKV-Induced Neuroinflammation and Cell Death in the Central Nervous System.

Zika virus (ZIKV) infection can cause severe neurological complications, particularly when antiviral immune responses are impaired. Here, we investigated how type I interferon (IFN-I) signaling influences the cellular inflammatory response and immunopathology in the central nervous system (CNS) during ZIKV infection. ZIKV infection induced early IFN-α and IFN-β expression in the CNS of wild-type (WT) mice. In contrast, mice lacking the IFN-I receptor (IFNAR-/-) exhibited higher CNS viral loads, severe clinical symptoms, weight loss, increased mortality, and histopathological alterations characterized by extensive leukocyte accumulation and ZIKV antigen detection. Flow cytometry and UMAP analysis revealed that IFN-I signaling restrains leukocyte accumulation in the CNS. IFNAR-/-mice showed increased accumulation of myeloid and lymphoid cells, including inflammatory monocytes, monocyte-derived dendritic cells, and activated CD4+ and CD8+ T cells, whereas WT mice displayed limited leukocyte accumulation. Loss of IFN-I signaling was associated with elevated levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF, and IFN-γ), chemokines (CCL2, CCL4, and CCL5), and inducible nitric oxide synthase (iNOS). Notably, CNS-resident microglia from IFNAR-/- mice were highly susceptible to cell death, including among ZIKV antigen-negative cells, suggesting that inflammatory signals generated during infection may contribute to injury in uninfected microglia. In contrast, myeloid cells were predominantly ZIKV antigen-positive but remained largely viable. CD45- non-leukocyte cells constituted the major ZIKV antigen-positive population in the CNS and displayed resistance to cell death, indicating that this compartment may represent an important cellular population associated with ZIKV antigen detection during acute infection. Together, these findings demonstrate that IFN-I signaling is essential for controlling ZIKV replication, restraining neuroinflammation, and limiting CNS immunopathology. Its absence leads to increased viral burden, dysregulated immune cell accumulation, and severe neurological disease.