Análise proteômica espacial do desenvolvimento da síndrome congênita do Zika

Abstract

Congenital infection by Zika virus (ZIKV) can lead to a broad clinical spectrum, ranging from severe microcephaly to milder neurological alterations characteristic of Congenital Zika Syndrome (CZS). This study employed a late-infection murine model (P0–P10) to investigate region-specific proteomic alterations in neonatal mouse brains caused by Zika virus (ZIKV) exposure. Seven brain regions were analyzed using bottom-up proteomics with data-independent acquisition (DIA) mass spectrometry. A total of 8,192 proteins were identified, and 5,298 were quantified. Multivariate analyses revealed distinct proteomic signatures, with the cerebellum (CB) and olfactory bulb (BL) presenting the highest number of differentially abundant and exclusive proteins, indicating regional tropism of the virus. Functional enrichment analysis highlighted ZIKV-induced modulation of synaptic and bioenergetic pathways. Significant downregulation of synaptic proteins such as Gad1/2, Gria1/2, Shank3, and Camk2a was observed in the hippocampus (HC), cerebral cortex (CX), CB, and BL, suggesting widespread disruption of neuronal connectivity. Moreover, mitochondrial dysfunction was evidenced by reduced abundance of electron transport chain subunits (complexes I, III, and V), particularly in CB and brainstem (BS), potentially compromising ATP production and cellular homeostasis. Altogether, these findings demonstrate that even mild ZIKV infection can drive region-specific molecular disturbances with implications for long-term neurological outcomes. The identification of disrupted synaptic and cellular energy signatures provides new insights into the neuropathogenesis of CZS and offers a foundation for future therapeutic strategies targeting regionally vulnerable brain circuits. Keywords: