Defining Mechanisms of Neurodevelopmental Injury in Congenital Zika Virus Infection

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ID: 327329
2026
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Abstract
Abstract Background Congenital infection by Zika virus (ZIKV) can cause neurodevelopmental abnormalities, ranging from microcephaly to fetal demise. With no approved antivirals or vaccines, defining how ZIKV mediates neurodevelopmental injury is an essential research goal. Our previous work demonstrated that neurons infected with ZIKV demonstrate decreased expression of genes vital for functioning synapses, suggesting that synapse loss may be an important mechanism of ZIKV-mediated neurologic injury. One possible pathway for virus-driven synapse loss is via induction of the secreted protein acidic and cysteine rich (SPARC) protein, which disrupts the extracellular matrix (ECM) adhesions between neurons.1 We hypothesize that ZIKV-induced SPARC causes synapse loss via ECM remodeling. Methods We isolated human primary neurons from fetal brain explants (HFB), infecting them with a wild-type Brazilian ZIKV or mock and harvesting at 2, 4, and 6 days post-infection to determine the time course of infection using immunofluorescence assay (IFA).To determine optimal SPARC knockdown conditions, cells were transfected with SPARC-targeting siRNA (Integrated DNA Technologies - IDT) or non-targeting control (NTC). Protein lysates were collected at 72 hours post-transfection and Western blot was performed to assess knockdown efficiency and synaptic protein expression (Figure 1). For comprehensive synapse analysis, HFB neurons were infected with ZIKV with and without SPARC knockdown. Immunofluorescence using antibodies against ZIKV, synaptophysin, and Homer-1 was performed and imaged with confocal microscopy using Fiji ImageJ software. Synapse density was then quantified by colocalization analysis of synaptophysin and Homer-1 puncta using SynBot software. Results We found that synapse density progressively declined over 6 days of ZIKV infection (pooled analysis: 17.6 synapses per infected cell vs. 25.59 for mock, p=0.0568). Western Blot confirmed the effectiveness of siRNA-mediated SPARC knockdown (Figure 1). For the colocalization analysis, we found ZIKV-infected cells with non-targeting control siRNA had an average of 2.47 synapses per cell, versus 6.23 synapses in ZIKV-infected cells with SPARC knockdown (p=0.0025; Table 1). Mock-infected cells showed a trend toward increased synapse density with SPARC knockdown (6.23 in non-targeting control vs 10.44 with knockdown; p=0.099). Conclusion ZIKV infection leads to maximal synapse loss in human fetal brain neurons at 6 days post infection. Furthermore, siRNA-mediated SPARC knockdown was achieved without altering synaptophysin-1 expression, validating the specificity of the knockdown approach. Colocalization analysis of synaptophysin and Homer1 puncta demonstrates that SPARC knockdown significantly reduced ZIKV-induced synapse loss, suggesting SPARC may be a therapeutic target to preserve synapse function during congenital ZIKV infection.
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Authors Dhyana Magesh, Dante Moreno, Savan Ram, Christina Adams Waldorf, Caleb Stokes
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Journal journal of the pediatric infectious diseases society
Year 2026
DOI
10.1093/jpids/piag070/piag070.006
URL
https://academic.oup.com/jpids/article-pdf/15/Supplement_2/S3/70833179/piag070.006.pdf
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