Spatially Resolved Microglial State Transitions Govern Strain-Specific Zika Neuropathogenesis

Abstract

Neurotropic viruses disrupt brain homeostasis through complex interactions among infected cells, resident immune responses, and tissue architecture, yet how these processes unfold across space, time, and cell types, and how viral strain differences shape disease severity, remains poorly understood. Here, we integrate high-resolution spatial transcriptomics with infection-aware cell-type profiling to construct a spatiotemporal atlas of Zika virus (ZIKV) infection in the mouse brain. Comparing Asian and African ZIKV strains across early and late infection stages, we uncover structured, strain-dependent reorganization of immune and structural cell populations that defines discrete infection-associated tissue niches. Microglia undergo region-specific state transitions characterized by both cell-intrinsic antiviral programs and widespread bystander activation, producing tissue-wide immune amplification. In Asian strain infection, we identify disease-associated microglia (DAM) as critical mediators of infection containment: DAM accumulate in regions where viral burden stabilizes, are promoted by Apoe-Trem2 signaling from infected cells and are governed by transcription regulators that restrain inflammatory programs while preserving phagocytic and antiviral functions. In contrast, African strain infection is marked by impaired Apoe-Trem2 signaling, persistent inflammatory microglial activation, and failure of containment. Progressive infection leads to depletion of oligodendrocytes, astrocytes, and neurons, loss of local cellular diversity and disruption of tissue architecture concentrated in somatosensory and motor regions associated with myelination and synaptic programs. These architectural disruptions correlate with severe neurological phenotypes in African strain infection and are preceded by transcriptional dysregulation in infected glial cells, including sustained stress responses, inflammatory signaling, and suppression of myelination and homeostatic pathways. Together, our study establishes a spatially resolved framework linking viral strain-specific microglial states to tissue disorganization and neurological functional impairment, providing mechanistic insight into how neurotropic viruses reshape microenvironments to drive neurological disease.