Type I IFN coordinates resistance and tolerance against Zika virus disease by inducing NK cell recruitment and limiting neutrophil-driven neuropathology in the brain

Abstract

Zika virus (ZIKV) neurological disease arises from both direct viral cytopathic effects in the central nervous system (CNS) and host-driven neuroinflammation, with disease outcomes determined by the balance between antiviral resistance and disease tolerance. Type I interferons (IFN-I) are well-established antiviral mediators that also regulate neuroinflammation and preserve blood–brain barrier (BBB) integrity. Previous in vitro studies showed that the African-lineage ZIKV strain MR766 (ZIKVMR766) is more resistant to IFN-I–mediated antiviral effects than the Asian-lineage strain PE243 (ZIKVPE243), suggesting that strain-specific interactions with IFN-I might shape disease outcome. Here, we used an intracerebroventricular (i.c.v.) inoculation model that enables CNS infection in wild-type (WT) mice and comparison with IFNAR-deficient (IfnR−/−) animals. Viral replication, neurological outcomes, BBB integrity, cytokine expression, and immune-cell infiltration and impact were assessed by plaque assay, behavioral analysis, RT-qPCR, flow cytometry, and antibody-mediated cell depletion. We demonstrate that IFN-I mediated antiviral resistance during ZIKVPE243 infection, as IfnR−/− mice exhibited significantly increased viral loads and mortality. In contrast, during ZIKVMR766 infection, viral loads were comparable, yet IFNAR deficiency led to accelerated neurological disease and death. Lethal outcomes were associated with significant BBB disruption and neutrophil infiltration, and depletion of neutrophils reduced disease severity without altering viral load. Conversely, NK cells were preferentially recruited to the CNS in WT mice, and their depletion increased viral titers, without altering disease progression. Together, these findings show that type I IFN coordinates resistance and disease tolerance to ZIKV infection by promoting NK cell recruitment to the CNS while limiting neutrophil-driven neuroinflammation.